Use of picolinamide compounds with fungicidal activity

ABSTRACT

This disclosure relates to picolinamides of Formula I and their use as fungicides.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. Nos. 62/098,089 filed Dec. 30, 2014, 62/098,097 filedDec. 30, 2014, 62/255,144 filed Nov. 13, 2015, 62/255,152 filed Nov. 13,2015, 62/255,163 filed Nov. 13, 2015, 62/255,168 filed Nov. 13, 2015,62/255,125 filed Nov. 13, 2015 and 62/255,131 filed Nov. 13, 2015, whichare expressly incorporated by reference herein.

BACKGROUND & SUMMARY

The present disclosure relates to picolinamides and their use asfungicides. The compounds of the present disclosure may offer protectionagainst ascomycetes, basidiomycetes, deuteromycetes and oomycetes.

One embodiment of the present disclosure may include compounds ofFormula I:

X is hydrogen or C(O)R₅;

Y is hydrogen, C(O)R₅, or Q;

Q is

R₁ and R₁₁ are independently chosen from hydrogen or alkyl, optionallysubstituted with 0, 1 or multiple R₈; Alternatively, R₁ and R₁₁ may betaken together to form a 3-6 membered saturated or partially saturatedcarbocycle or heterocycle, optionally substituted with 0, 1 or multipleR₈;

R₂ and R₁₂ are independently chosen from hydrogen, alkyl, aryl, oralkenyl, each optionally substituted with 0, 1 or multiple R;

R₃ is chosen from hydrogen, C₂-C₆ alkyl, aryl, or alkenyl, eachoptionally substituted with 0, 1 or multiple R₈;

R₄ is chosen from alkyl, aryl, or acyl, each optionally substituted with0, 1 or multiple R₈;

R₅ is chosen from alkoxy or benzyloxy, each optionally substituted with0, 1, or multiple R₈;

R₆ is chosen from hydrogen, alkoxy, or halo, each optionally substitutedwith 0, 1, or multiple R₈;

R₇ is chosen from hydrogen, —C(O)R₉, or —CH₂OC(O)R₉;

R₈ is chosen from hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkoxy, orheterocyclyl, each optionally substituted with 0, 1, or multiple R₁₀;

R₉ is chosen from alkyl, alkoxy, or aryl, each optionally substitutedwith 0, 1, or multiple R₈;

R₁₀ is chosen from hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkoxy,or heterocyclyl.

Another embodiment of the present disclosure may include a fungicidalcomposition for the control or prevention of fungal attack comprisingthe compounds described above and a phytologically acceptable carriermaterial.

Yet another embodiment of the present disclosure may include a methodfor the control or prevention of fungal attack on a plant, the methodincluding the steps of applying a fungicidally effective amount of oneor more of the compounds described above to at least one of the fungus,the plant, and an area adjacent to the plant.

It will be understood by those skilled in the art that the followingterms may include generic “R”-groups within their definitions, e.g.,“the term alkoxy refers to an —OR substituent”. It is also understoodthat within the definitions for the following terms, these “R” groupsare included for illustration purposes and should not be construed aslimiting or being limited by substitutions about Formula I.

The term “alkyl” refers to a branched, unbranched, or saturated cycliccarbon chain, including, but not limited to, methyl, ethyl, propyl,butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term “alkenyl” refers to a branched, unbranched or cyclic carbonchain containing one or more double bonds including, but not limited to,ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, and the like.

The term “alkynyl” refers to a branched or unbranched carbon chaincontaining one or more triple bonds including, but not limited to,propynyl, butynyl, and the like.

The terms “aryl” and “Ar” refer to any aromatic ring, mono- orbi-cyclic, containing 0 heteroatoms.

The term “heterocyclyl” refers to any aromatic or non-aromatic ring,mono- or bi-cyclic, containing one or more heteroatoms

The term “alkoxy” refers to an —OR substituent.

The term “acyloxy” refers to an —OC(O)R substituent.

The term “cyano” refers to a —C≡N substituent.

The term “hydroxyl” refers to an —OH substituent.

The term “amino” refers to a —N(R)₂ substituent.

The term “arylalkoxy” refers to —O(CH₂)_(n)Ar where n is an integerselected from the list 1, 2, 3, 4, 5, or 6.

The term “haloalkoxy” refers to an —OR—X substituent, wherein X is Cl,F, Br, or I, or any combination thereof.

The term “haloalkyl” refers to an alkyl, which is substituted with Cl,F, I, or Br or any combination thereof.

The term “halogen” or “halo” refers to one or more halogen atoms,defined as F, Cl, Br, and I.

The term “nitro” refers to a —NO₂ substituent.

The term thioalkyl refers to an —SR substituent.

Throughout the disclosure, reference to the compounds of Formula I isread as also including all stereoisomers, for example diastereomers,enantiomers, and mixtures thereof. In another embodiment, Formula (I) isread as also including salts or hydrates thereof. Exemplary saltsinclude, but are not limited to: hydrochloride, hydrobromide,hydroiodide, trifluoroacetate, and trifluoromethane sulfonate.

It is also understood by those skilled in the art that additionalsubstitution is allowable, unless otherwise noted, as long as the rulesof chemical bonding and strain energy are satisfied and the productstill exhibits fungicidal activity.

Another embodiment of the present disclosure is a use of a compound ofFormula I, for protection of a plant against attack by a phytopathogenicorganism or the treatment of a plant infested by a phytopathogenicorganism, comprising the application of a compound of Formula I, or acomposition comprising the compound to soil, a plant, a part of a plant,foliage, and/or roots.

Additionally, another embodiment of the present disclosure is acomposition useful for protecting a plant against attack by aphytopathogenic organism and/or treatment of a plant infested by aphytopathogenic organism comprising a compound of Formula I and aphytologically acceptable carrier material.

DETAILED DESCRIPTION

The compounds of the present disclosure may be applied by any of avariety of known techniques, either as the compounds or as formulationscomprising the compounds. For example, the compounds may be applied tothe roots or foliage of plants for the control of various fungi, withoutdamaging the commercial value of the plants. The materials may beapplied in the form of any of the generally used formulation types, forexample, as solutions, dusts, wettable powders, flowable concentrate, oremulsifiable concentrates.

Preferably, the compounds of the present disclosure are applied in theform of a formulation, comprising one or more of the compounds ofFormula I with a phytologically acceptable carrier. Concentratedformulations may be dispersed in water, or other liquids, forapplication, or formulations may be dust-like or granular, which maythen be applied without further treatment. The formulations can beprepared according to procedures that are conventional in theagricultural chemical art.

The present disclosure contemplates all vehicles by which one or more ofthe compounds may be formulated for delivery and use as a fungicide.Typically, formulations are applied as aqueous suspensions or emulsions.Such suspensions or emulsions may be produced from water-soluble,water-suspendable, or emulsifiable formulations which are solids,usually known as wettable powders; or liquids, usually known asemulsifiable concentrates, aqueous suspensions, or suspensionconcentrates. As will be readily appreciated, any material to whichthese compounds may be added may be used, provided it yields the desiredutility without significant interference with the activity of thesecompounds as antifungal agents.

Wettable powders, which may be compacted to form water-dispersiblegranules, comprise an intimate mixture of one or more of the compoundsof Formula I, an inert carrier and surfactants. The concentration of thecompound in the wettable powder may be from about 10 percent to about 90percent by weight based on the total weight of the wettable powder, morepreferably about 25 weight percent to about 75 weight percent. In thepreparation of wettable powder formulations, the compounds may becompounded with any finely divided solid, such as prophyllite, talc,chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein,gluten, montmorillonite clays, diatomaceous earths, purified silicatesor the like. In such operations, the finely divided carrier andsurfactants are typically blended with the compound(s) and milled.

Emulsifiable concentrates of the compounds of Formula I may comprise aconvenient concentration, such as from about 1 weight percent to about50 weight percent of the compound, in a suitable liquid, based on thetotal weight of the concentrate. The compounds may be dissolved in aninert carrier, which is either a water-miscible solvent or a mixture ofwater-immiscible organic solvents, and emulsifiers. The concentrates maybe diluted with water and oil to form spray mixtures in the form ofoil-in-water emulsions. Useful organic solvents include aromatics,especially the high-boiling naphthalenic and olefinic portions ofpetroleum such as heavy aromatic naphtha. Other organic solvents mayalso be used, for example, terpenic solvents, including rosinderivatives, aliphatic ketones, such as cyclohexanone, and complexalcohols, such as 2-ethoxyethanol.

Emulsifiers which may be advantageously employed herein may be readilydetermined by those skilled in the art and include various nonionic,anionic, cationic and amphoteric emulsifiers, or a blend of two or moreemulsifiers. Examples of nonionic emulsifiers useful in preparing theemulsifiable concentrates include the polyalkylene glycol ethers andcondensation products of alkyl and aryl phenols, aliphatic alcohols,aliphatic amines or fatty acids with ethylene oxide, propylene oxidessuch as the ethoxylated alkyl phenols and carboxylic esters solubilizedwith the polyol or polyoxyalkylene. Cationic emulsifiers includequaternary ammonium compounds and fatty amine salts. Anionic emulsifiersinclude the oil-soluble salts (e.g., calcium) of alkylaryl sulphonicacids, oil-soluble salts or sulfated polyglycol ethers and appropriatesalts of phosphated polyglycol ether.

Representative organic liquids which may be employed in preparing theemulsifiable concentrates of the compounds of the present disclosure arethe aromatic liquids such as xylene, propyl benzene fractions; or mixednaphthalene fractions, mineral oils, substituted aromatic organicliquids such as dioctyl phthalate; kerosene; dialkyl amides of variousfatty acids, particularly the dimethyl amides of fatty glycols andglycol derivatives such as the n-butyl ether, ethyl ether or methylether of diethylene glycol, the methyl ether of triethylene glycol,petroleum fractions or hydrocarbons such as mineral oil, aromaticsolvents, paraffinic oils, and the like; vegetable oils such as soy beanoil, rape seed oil, olive oil, castor oil, sunflower seed oil, coconutoil, corn oil, cotton seed oil, linseed oil, palm oil, peanut oil,safflower oil, sesame oil, tung oil and the like; esters of the abovevegetable oils; and the like. Mixtures of two or more organic liquidsmay also be employed in the preparation of the emulsifiable concentrate.Organic liquids include xylene, and propyl benzene fractions, withxylene being most preferred in some cases. Surface-active dispersingagents are typically employed in liquid formulations and in an amount offrom 0.1 to 20 percent by weight based on the combined weight of thedispersing agent with one or more of the compounds. The formulations canalso contain other compatible additives, for example, plant growthregulators and other biologically active compounds used in agriculture.

Aqueous suspensions comprise suspensions of one or more water-insolublecompounds of Formula I, dispersed in an aqueous vehicle at aconcentration in the range from about 1 to about 50 weight percent,based on the total weight of the aqueous suspension. Suspensions areprepared by finely grinding one or more of the compounds, and vigorouslymixing the ground material into a vehicle comprised of water andsurfactants chosen from the same types discussed above. Othercomponents, such as inorganic salts and synthetic or natural gums, mayalso be added to increase the density and viscosity of the aqueousvehicle.

The compounds of Formula I can also be applied as granular formulations,which are particularly useful for applications to the soil. Granularformulations generally contain from about 0.5 to about 10 weightpercent, based on the total weight of the granular formulation of thecompound(s), dispersed in an inert carrier which consists entirely or inlarge part of coarsely divided inert material such as attapulgite,bentonite, diatomite, clay or a similar inexpensive substance. Suchformulations are usually prepared by dissolving the compounds in asuitable solvent and applying it to a granular carrier which has beenpreformed to the appropriate particle size, in the range of from about0.5 to about 3 mm. A suitable solvent is a solvent in which the compoundis substantially or completely soluble. Such formulations may also beprepared by making a dough or paste of the carrier and the compound andsolvent, and crushing and drying to obtain the desired granularparticle.

Dusts containing the compounds of Formula I may be prepared byintimately mixing one or more of the compounds in powdered form with asuitable dusty agricultural carrier, such as, for example, kaolin clay,ground volcanic rock, and the like. Dusts can suitably contain fromabout 1 to about 10 weight percent of the compounds, based on the totalweight of the dust.

The formulations may additionally contain adjuvant surfactants toenhance deposition, wetting, and penetration of the compounds onto thetarget crop and organism. These adjuvant surfactants may optionally beemployed as a component of the formulation or as a tank mix. The amountof adjuvant surfactant will typically vary from 0.01 to 1.0 percent byvolume, based on a spray-volume of water, preferably 0.05 to 0.5 volumepercent. Suitable adjuvant surfactants include, but are not limited toethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols,salts of the esters or sulphosuccinic acids, ethoxylatedorganosilicones, ethoxylated fatty amines, blends of surfactants withmineral or vegetable oils, crop oil concentrate (mineral oil(85%)+emulsifiers (15%)); nonylphenol ethoxylate;benzylcocoalkyldimethyl quaternary ammonium salt; blend of petroleumhydrocarbon, alkyl esters, organic acid, and anionic surfactant; C₉-C₁₁alkylpolyglycoside; phosphated alcohol ethoxylate; natural primaryalcohol (C₁₂-C₁₆) ethoxylate; di-sec-butylphenol EO-PO block copolymer;polysiloxane-methyl cap; nonylphenol ethoxylate+urea ammonium nitrate;emulsified methylated seed oil; tridecyl alcohol (synthetic) ethoxylate(8EO); tallow amine ethoxylate (15 EO); PEG(400) dioleate-99. Theformulations may also include oil-in-water emulsions such as thosedisclosed in U.S. patent application Ser. No. 11/495,228, the disclosureof which is expressly incorporated by reference herein.

The formulations may optionally include combinations that contain otherpesticidal compounds. Such additional pesticidal compounds may befungicides, insecticides, herbicides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present disclosure in the mediumselected for application, and not antagonistic to the activity of thepresent compounds. Accordingly, in such embodiments, the otherpesticidal compound is employed as a supplemental toxicant for the sameor for a different pesticidal use. The compounds of Formula I and thepesticidal compound in the combination can generally be present in aweight ratio of from 1:100 to 100:1.

The compounds of the present disclosure may also be combined with otherfungicides to form fungicidal mixtures and synergistic mixtures thereof.The fungicidal compounds of the present disclosure are often applied inconjunction with one or more other fungicides to control a wider varietyof undesirable diseases. When used in conjunction with otherfungicide(s), the presently claimed compounds may be formulated with theother fungicide(s), tank-mixed with the other fungicide(s) or appliedsequentially with the other fungicide(s). Such other fungicides mayinclude 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol,8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin,Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus subtilis,Bacillus subtilis strain QST713, benalaxyl, benomyl,benthiavalicarb-isopropyl, benzovindiflupyr benzylaminobenzene-sulfonate(BABS) salt, bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen,blasticidin-S, borax, Bordeaux mixture, boscalid, bromuconazole,bupirimate, calcium polysulfide, captafol, captan, carbendazim,carboxin, carpropamid, carvone, chlazafenone, chloroneb, chlorothalonil,chlozolinate, Coniothyrium minitans, copper hydroxide, copper octanoate,copper oxychloride, copper sulfate, copper sulfate (tribasic), cuprousoxide, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil,dazomet, debacarb, diammonium ethylenebis-(dithiocarbamate),dichlofluanid, dichlorophen, diclocymet, diclomezine, dichloran,diethofencarb, difenoconazole, difenzoquat ion, diflumetorim,dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton,dinocap, diphenylamine, dithianon, dodemorph, dodemorph acetate, dodine,dodine free base, edifenphos, enestrobin, enestroburin, epoxiconazole,ethaboxam, ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil,fenpropidin, fenpropimorph, fenpyrazamine, fentin, fentin acetate,fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumorph,fluopicolide, fluopyram, fluoroimide, fluoxastrobin, fluquinconazole,flusilazole, flusulfamide, flutianil, flutolanil, flutriafol,fluxapyroxad, folpet, formaldehyde, fosetyl, fosetyl-aluminium,fuberidazole, furalaxyl, furametpyr, guazatine, guazatine acetates,GY-81, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imazalilsulfate, imibenconazole, iminoctadine, iminoctadine triacetate,iminoctadine tris(albesilate), iodocarb, ipconazole, ipfenpyrazolone,iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopyrazam,isotianil, kasugamycin, kasugamycin hydrochloride hydrate,kresoxim-methyl, laminarin, mancopper, mancozeb, mandipropamid, maneb,mefenoxam, mepanipyrim, mepronil, meptyl-dinocap, mercuric chloride,mercuric oxide, mercurous chloride, metalaxyl, metalaxyl-M, metam,metam-ammonium, metam-potassium, metam-sodium, metconazole,methasulfocarb, methyl iodide, methyl isothiocyanate, metiram,metominostrobin, metrafenone, mildiomycin, myclobutanil, nabam,nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic acid (fattyacids), orysastrobin, oxadixyl, oxine-copper, oxpoconazole fumarate,oxycarboxin, pefurazoate, penconazole, pencycuron, penflufen,pentachlorophenol, pentachlorophenyl laurate, penthiopyrad,phenylmercury acetate, phosphonic acid, phthalide, picoxystrobin,polyoxin B, polyoxins, polyoxorim, potassium bicarbonate, potassiumhydroxyquinoline sulfate, probenazole, prochloraz, procymidone,propamocarb, propamocarb hydrochloride, propiconazole, propineb,proquinazid, prothioconazole, pyraclostrobin, pyrametostrobin,pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox,pyrimethanil, pyriofenone, pyroquilon, quinoclamine, quinoxyfen,quintozene, Reynoutria sachalinensis extract, sedaxane, silthiofam,simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodiumpentachlorophenoxide, spiroxamine, sulfur, SYP-Z048, tar oils,tebuconazole, tebufloquin, tecnazene, tetraconazole, thiabendazole,thifluzamide, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl,tolylfluanid, triadimefon, triadimenol, triazoxide, tricyclazole,tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole,validamycin, valifenalate, valiphenal, vinclozolin, zineb, ziram,zoxamide, Candida oleophila, Fusarium oxysporum, Gliocladium spp.,Phlebiopsis gigantea, Streptomyces griseoviridis, Trichoderma spp.,(RS)—N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide,1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate,1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane,2-(2-heptadecyl-2-imidazolin-1-yl)ethanol,2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide,2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride,2-methoxyethylmercury silicate, 3-(4-chlorophenyl)-5-methylrhodanine,4-(2-nitroprop-1-enyl)phenyl thiocyanateme, ampropylfos, anilazine,azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox,bentaluron, benzamacril; benzamacril-isobutyl, benzamorf, binapacryl,bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate, cadmiumcalcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone,chloraniformethan, chlorfenazole, chlorquinox, climbazole, copperbis(3-phenylsalicylate), copper zinc chromate, cufraneb, cuprichydrazinium sulfate, cuprobam, cyclafuramid, cypendazole, cyprofuram,decafentin, dichlone, dichlozoline, diclobutrazol, dimethirimol,dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin,drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf,fenapanil, fenitropan, fluotrimazole, furcarbanil, furconazole,furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin,halacrinate, Hercules 3944, hexylthiofos, ICIA0858, isopamphos,isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam,methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride,myclozolin, N-3,5-dichlorophenyl-succinimide,N-3-nitrophenylitaconimide, natamycin,N-ethylmercurio-4-toluenesulfonanilide, nickelbis(dimethyldithiocarbamate), OCH, phenylmercurydimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, prothiocarb;prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyroxychlor,pyroxyfur, quinacetol; quinacetol sulfate, quinazamid, quinconazole,rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor,thicyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid,triamiphos, triarimol, triazbutil, trichlamide, urbacid, zarilamid, andany combinations thereof.

Additionally, the compounds described herein may be combined with otherpesticides, including insecticides, nematocides, miticides,arthropodicides, bactericides or combinations thereof that arecompatible with the compounds of the present disclosure in the mediumselected for application, and not antagonistic to the activity of thepresent compounds to form pesticidal mixtures and synergistic mixturesthereof. The fungicidal compounds of the present disclosure may beapplied in conjunction with one or more other pesticides to control awider variety of undesirable pests. When used in conjunction with otherpesticides, the presently claimed compounds may be formulated with theother pesticide(s), tank-mixed with the other pesticide(s) or appliedsequentially with the other pesticide(s). Typical insecticides include,but are not limited to: 1,2-dichloropropane, abamectin, acephate,acetamiprid, acethion, acetoprole, acrinathrin, acrylonitrile,alanycarb, aldicarb, aldoxycarb, aldrin, allethrin, allosamidin,allyxycarb, alpha-cypermethrin, alpha-ecdysone, alpha-endosulfan,amidithion, aminocarb, amiton, amiton oxalate, amitraz, anabasine,athidathion, azadirachtin, azamethiphos, azinphos-ethyl,azinphos-methyl, azothoate, barium hexafluorosilicate, barthrin,bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin,bifenthrin, bioallethrin, bioethanomethrin, biopermethrin, bistrifluron,borax, boric acid, bromfenvinfos, bromocyclen, bromo-DDT, bromophos,bromophos-ethyl, bufencarb, buprofezin, butacarb, butathiofos,butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate,calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran,carbon disulfide, carbon tetrachloride, carbophenothion, carbosulfan,cartap, cartap hydrochloride, chlorantraniliprole, chlorbicyclen,chlordane, chlordecone, chlordimeform, chlordimeform hydrochloride,chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron,chlormephos, chloroform, chloropicrin, chlorphoxim, chlorprazophos,chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, chromafenozide,cinerin I, cinerin II, cinerins, cismethrin, cloethocarb, closantel,clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate,copper oleate, coumaphos, coumithoate, crotamiton, crotoxyphos,crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate,cyantraniliprole, cyclethrin, cycloprothrin, cyfluthrin, cyhalothrin,cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran,deltamethrin, demephion, demephion-O, demephion-S, demeton,demeton-methyl, demeton-O, demeton-O-methyl, demeton-S,demeton-S-methyl, demeton-S-methylsulphon, diafenthiuron, dialifos,diatomaceous earth, diazinon, dicapthon, dichlofenthion, dichlorvos,dicresyl, dicrotophos, dicyclanil, dieldrin, diflubenzuron, dilor,dimefluthrin, dimefox, dimetan, dimethoate, dimethrin, dimethylvinphos,dimetilan, dinex, dinex-diclexine, dinoprop, dinosam, dinotefuran,diofenolan, dioxabenzofos, dioxacarb, dioxathion, disulfoton,dithicrofos, d-limonene, DNOC, DNOC-ammonium, DNOC-potassium,DNOC-sodium, doramectin, ecdysterone, emamectin, emamectin benzoate,EMPC, empenthrin, endosulfan, endothion, endrin, EPN, epofenonane,eprinomectin, esdepallethrine, esfenvalerate, etaphos, ethiofencarb,ethion, ethiprole, ethoate-methyl, ethoprophos, ethyl formate,ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide,etofenprox, etrimfos, EXD, famphur, fenamiphos, fenazaflor,fenchlorphos, fenethacarb, fenfluthrin, fenitrothion, fenobucarb,fenoxacrim, fenoxycarb, fenpirithrin, fenpropathrin, fensulfothion,fenthion, fenthion-ethyl, fenvalerate, fipronil, flonicamid,flubendiamide, flucofuron, flucycloxuron, flucythrinate, flufenerim,flufenoxuron, flufenprox, fluvalinate, fonofos, formetanate, formetanatehydrochloride, formothion, formparanate, formparanate hydrochloride,fosmethilan, fospirate, fosthietan, furathiocarb, furethrin,gamma-cyhalothrin, gamma-HCH, halfenprox, halofenozide, HCH, HEOD,heptachlor, heptenophos, heterophos, hexaflumuron, HHDN, hydramethylnon,hydrogen cyanide, hydroprene, hyquincarb, imidacloprid, imiprothrin,indoxacarb, iodomethane, IPSP, isazofos, isobenzan, isocarbophos,isodrin, isofenphos, isofenphos-methyl, isoprocarb, isoprothiolane,isothioate, isoxathion, ivermectin, jasmolin I, jasmolin II, jodfenphos,juvenile hormone I, juvenile hormone II, juvenile hormone III, kelevan,kinoprene, lambda-cyhalothrin, lead arsenate, lepimectin, leptophos,lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben,mazidox, mecarbam, mecarphon, menazon, mephosfolan, mercurous chloride,mesulfenfos, metaflumizone, methacrifos, methamidophos, methidathion,methiocarb, methocrotophos, methomyl, methoprene, methoxychlor,methoxyfenozide, methyl bromide, methyl isothiocyanate,methylchloroform, methylene chloride, metofluthrin, metolcarb,metoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime,mipafox, mirex, molosultap, monocrotophos, monomehypo, monosultap,morphothion, moxidectin, naftalofos, naled, naphthalene, nicotine,nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron,noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos,oxydisulfoton, para-dichlorobenzene, parathion, parathion-methyl,penfluron, pentachlorophenol, permethrin, phenkapton, phenothrin,phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor,phosphamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos,pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, potassium arsenite,potassium thiocyanate, pp′-DDT, prallethrin, precocene I, precocene II,precocene III, primidophos, profenofos, profluralin, promacyl,promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos,prothoate, protrifenbute, pyraclofos, pyrafluprole, pyrazophos,pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins, pyridaben,pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimitate,pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl,quinothion, rafoxanide, resmethrin, rotenone, ryania, sabadilla,schradan, selamectin, silafluofen, silica gel, sodium arsenite, sodiumfluoride, sodium hexafluorosilicate, sodium thiocyanate, sophamide,spinetoram, spinosad, spiromesifen, spirotetramat, sulcofuron,sulcofuron-sodium, sulfluramid, sulfotep, sulfoxaflor, sulfurylfluoride, sulprofos, tau-fluvalinate, tazimcarb, TDE, tebufenozide,tebufenpyrad, tebupirimfos, teflubenzuron, tefluthrin, temephos, TEPP,terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos,tetramethrin, tetramethylfluthrin, theta-cypermethrin, thiacloprid,thiamethoxam, thicrofos, thiocarboxime, thiocyclam, thiocyclam oxalate,thiodicarb, thiofanox, thiometon, thiosultap, thiosultap-disodium,thiosultap-monosodium, thuringiensin, tolfenpyrad, tralomethrin,transfluthrin, transpermethrin, triarathene, triazamate, triazophos,trichlorfon, trichlormetaphos-3, trichloronat, trifenofos, triflumuron,trimethacarb, triprene, vamidothion, vaniliprole, XMC, xylylcarb,zeta-cypermethrin, zolaprofos, and any combinations thereof.

Additionally, the compounds described herein may be combined withherbicides that are compatible with the compounds of the presentdisclosure in the medium selected for application, and not antagonisticto the activity of the present compounds to form pesticidal mixtures andsynergistic mixtures thereof. The fungicidal compounds of the presentdisclosure may be applied in conjunction with one or more herbicides tocontrol a wide variety of undesirable plants. When used in conjunctionwith herbicides, the presently claimed compounds may be formulated withthe herbicide(s), tank-mixed with the herbicide(s) or appliedsequentially with the herbicide(s). Typical herbicides include, but arenot limited to: 4-CPA; 4-CPB; 4-CPP; 2,4-D; 3,4-DA; 2,4-DB; 3,4-DB;2,4-DEB; 2,4-DEP; 3,4-DP; 2,3,6-TBA; 2,4,5-T; 2,4,5-TB; acetochlor,acifluorfen, aclonifen, acrolein, alachlor, allidochlor, alloxydim,allyl alcohol, alorac, ametridione, ametryn, amibuzin, amicarbazone,amidosulfuron, aminocyclopyrachlor, aminopyralid, amiprofos-methyl,amitrole, ammonium sulfamate, anilofos, anisuron, asulam, atraton,atrazine, azafenidin, azimsulfuron, aziprotryne, barban, BCPC,beflubutamid, benazolin, bencarbazone, benfluralin, benfuresate,bensulfuron, bensulide, bentazone, benzadox, benzfendizone, benzipram,benzobicyclon, benzofenap, benzofluor, benzoylprop, benzthiazuron,bicyclopyrone, bifenox, bilanafos, bispyribac, borax, bromacil,bromobonil, bromobutide, bromofenoxim, bromoxynil, brompyrazon,butachlor, butafenacil, butamifos, butenachlor, buthidazole, buthiuron,butralin, butroxydim, buturon, butylate, cacodylic acid, cafenstrole,calcium chlorate, calcium cyanamide, cambendichlor, carbasulam,carbetamide, carboxazole chlorprocarb, carfentrazone, CDEA, CEPC,chlomethoxyfen, chloramben, chloranocryl, chlorazifop, chlorazine,chlorbromuron, chlorbufam, chloreturon, chlorfenac, chlorfenprop,chlorflurazole, chlorflurenol, chloridazon, chlorimuron, chlornitrofen,chloropon, chlorotoluron, chloroxuron, chloroxynil, chlorpropham,chlorsulfuron, chlorthal, chlorthiamid, cinidon-ethyl, cinmethylin,cinosulfuron, cisanilide, clethodim, cliodinate, clodinafop, clofop,clomazone, clomeprop, cloprop, cloproxydim, clopyralid, cloransulam,CMA, copper sulfate, CPMF, CPPC, credazine, cresol, cumyluron,cyanatryn, cyanazine, cycloate, cyclosulfamuron, cycloxydim, cycluron,cyhalofop, cyperquat, cyprazine, cyprazole, cypromid, daimuron, dalapon,dazomet, delachlor, desmedipham, desmetryn, di-allate, dicamba,dichlobenil, dichloralurea, dichlormate, dichlorprop, dichlorprop-P,diclofop, diclosulam, diethamquat, diethatyl, difenopenten, difenoxuron,difenzoquat, diflufenican, diflufenzopyr, dimefuron, dimepiperate,dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, dimexano,dimidazon, dinitramine, dinofenate, dinoprop, dinosam, dinoseb,dinoterb, diphenamid, dipropetryn, diquat, disul, dithiopyr, diuron,DMPA, DNOC, DSMA, EBEP, eglinazine, endothal, epronaz, EPTC, erbon,esprocarb, ethalfluralin, ethametsulfuron, ethidimuron, ethiolate,ethofumesate, ethoxyfen, ethoxysulfuron, etinofen, etnipromid,etobenzanid, EXD, fenasulam, fenoprop, fenoxaprop, fenoxaprop-P,fenoxasulfone, fenteracol, fenthiaprop, fentrazamide, fenuron, ferroussulfate, flamprop, flamprop-M, flazasulfuron, florasulam, fluazifop,fluazifop-P, fluazolate, flucarbazone, flucetosulfuron, fluchloralin,flufenacet, flufenican, flufenpyr, flumetsulam, flumezin, flumiclorac,flumioxazin, flumipropyn, fluometuron, fluorodifen, fluoroglycofen,fluoromidine, fluoronitrofen, fluothiuron, flupoxam, flupropacil,flupropanate, flupyrsulfuron, fluridone, flurochloridone, fluroxypyr,flurtamone, fluthiacet, fomesafen, foramsulfuron, fosamine, furyloxyfen,glufosinate, glufosinate-P, glyphosate, halauxifen, halosafen,halosulfuron, haloxydine, haloxyfop, haloxyfop-P, hexachloroacetone,hexaflurate, hexazinone, imazamethabenz, imazamox, imazapic, imazapyr,imazaquin, imazethapyr, imazosulfuron, indanofan, indaziflam, iodobonil,iodomethane, iodosulfuron, ioxynil, ipazine, ipfencarbazone, iprymidam,isocarbamid, isocil, isomethiozin, isonoruron, isopolinate, isopropalin,isoproturon, isouron, isoxaben, isoxachlortole, isoxaflutole,isoxapyrifop, karbutilate, ketospiradox, lactofen, lenacil, linuron,MAA, MAMA, MCPA, MCPA-thioethyl, MCPB, mecoprop, mecoprop-P, medinoterb,mefenacet, mefluidide, mesoprazine, mesosulfuron, mesotrione, metam,metamifop, metamitron, metazachlor, metazosulfuron, metflurazon,methabenzthiazuron, methalpropalin, methazole, methiobencarb,methiozolin, methiuron, methometon, methoprotryne, methyl bromide,methyl isothiocyanate, methyldymron, metobenzuron, metobromuron,metolachlor, metosulam, metoxuron, metribuzin, metsulfuron, molinate,monalide, monisouron, monochloroacetic acid, monolinuron, monuron,morfamquat, MSMA, naproanilide, napropamide, naptalam, neburon,nicosulfuron, nipyraclofen, nitralin, nitrofen, nitrofluorfen,norflurazon, noruron, OCH, orbencarb, ortho-dichlorobenzene,orthosulfamuron, oryzalin, oxadiargyl, oxadiazon, oxapyrazon,oxasulfuron, oxaziclomefone, oxyfluorfen, parafluron, paraquat,pebulate, pelargonic acid, pendimethalin, penoxsulam, pentachlorophenol,pentanochlor, pentoxazone, perfluidone, pethoxamid, phenisopham,phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercury acetate,picloram, picolinafen, pinoxaden, piperophos, potassium arsenite,potassium azide, potassium cyanate, pretilachlor, primisulfuron,procyazine, prodiamine, profluazol, profluralin, profoxydim,proglinazine, prometon, prometryn, propachlor, propanil, propaquizafop,propazine, propham, propisochlor, propoxycarbazone, propyrisulfuron,propyzamide, prosulfalin, prosulfocarb, prosulfuron, proxan, prynachlor,pydanon, pyraclonil, pyraflufen, pyrasulfotole, pyrazolynate,pyrazosulfuron, pyrazoxyfen, pyribenzoxim, pyributicarb, pyriclor,pyridafol, pyridate, pyriftalid, pyriminobac, pyrimisulfan, pyrithiobac,pyroxasulfone, pyroxsulam, quinclorac, quinmerac, quinoclamine,quinonamid, quizalofop, quizalofop-P, rhodethanil, rimsulfuron,saflufenacil, S-metolachlor, sebuthylazine, secbumeton, sethoxydim,siduron, simazine, simeton, simetryn, SMA, sodium arsenite, sodiumazide, sodium chlorate, sulcotrione, sulfallate, sulfentrazone,sulfometuron, sulfosulfuron, sulfuric acid, sulglycapin, swep, TCA,tebutam, tebuthiuron, tefuryltrione, tembotrione, tepraloxydim,terbacil, terbucarb, terbuchlor, terbumeton, terbuthylazine, terbutryn,tetrafluron, thenylchlor, thiazafluron, thiazopyr, thidiazimin,thidiazuron, thiencarbazone-methyl, thifensulfuron, thiobencarb,tiocarbazil, tioclorim, topramezone, tralkoxydim, triafamone,tri-allate, triasulfuron, triaziflam, tribenuron, tricamba, triclopyr,tridiphane, trietazine, trifloxysulfuron, trifluralin, triflusulfuron,trifop, trifopsime, trihydroxytriazine, trimeturon, tripropindan,tritac, tritosulfuron, vernolate, and xylachlor.

Another embodiment of the present disclosure is a method for the controlor prevention of fungal attack. This method comprises applying to thesoil, plant, roots, foliage, or locus of the fungus, or to a locus inwhich the infestation is to be prevented (for example applying to cerealor grape plants), a fungicidally effective amount of one or more of thecompounds of Formula I. The compounds are suitable for treatment ofvarious plants at fungicidal levels, while exhibiting low phytotoxicity.The compounds may be useful both in a protectant and/or an eradicantfashion.

The compounds have been found to have significant fungicidal effectparticularly for agricultural use. Many of the compounds areparticularly effective for use with agricultural crops and horticulturalplants.

It will be understood by those skilled in the art that the efficacy ofthe compound for the foregoing fungi establishes the general utility ofthe compounds as fungicides.

The compounds have broad ranges of activity against fungal pathogens.Exemplary pathogens may include, but are not limited to, causing agentof wheat leaf blotch (Zymoseptoria tritici), wheat brown rust (Pucciniatriticina), wheat stripe rust (Puccinia striiformis), scab of apple(Venturia inaequalis), powdery mildew of grapevine (Uncinula necator),barley scald (Rhynchosporium secalis), blast of rice (Pyriculariaoryzae), rust of soybean (Phakopsora pachyrhizi), glume blotch of wheat(Leptosphaeria nodorum), powdery mildew of wheat (Blumeria graminis f.sp.tritici), powdery mildew of barley (Blumeria graminis f. sp. hordei),powdery mildew of cucurbits (Erysiphe cichoracearum), anthracnose ofcucurbits (Colletotrichum lagenarium), leaf spot of beet (Cercosporabeticola), early blight of tomato (Alternaria solani), and spot blotchof barley (Cochliobolus sativus). The exact amount of the activematerial to be applied is dependent not only on the specific activematerial being applied, but also on the particular action desired, thefungal species to be controlled, and the stage of growth thereof, aswell as the part of the plant or other product to be contacted with thecompound. Thus, all the compounds, and formulations containing the same,may not be equally effective at similar concentrations or against thesame fungal species.

The compounds are effective in use with plants in a disease-inhibitingand phytologically acceptable amount. The term “disease-inhibiting andphytologically acceptable amount” refers to an amount of a compound thatkills or inhibits the plant disease for which control is desired, but isnot significantly toxic to the plant. This amount will generally be fromabout 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm beingpreferred. The exact concentration of compound required varies with thefungal disease to be controlled, the type of formulation employed, themethod of application, the particular plant species, climate conditions,and the like. A suitable application rate is typically in the range fromabout 0.10 to about 4 pounds/acre (about 0.01 to 0.45 grams per squaremeter, g/m²).

Any range or desired value given herein may be extended or alteredwithout losing the effects sought, as is apparent to the skilled personfor an understanding of the teachings herein.

The compounds of Formula I may be made using well-known chemicalprocedures. Intermediates not specifically mentioned in this disclosureare either commercially available, may be made by routes disclosed inthe chemical literature, or may be readily synthesized from commercialstarting materials utilizing standard procedures.

General Schemes

The following schemes illustrate approaches to generating picolinamidecompounds of Formula (I). The following descriptions and examples areprovided for illustrative purposes and should not be construed aslimiting in terms of substituents or substitution patterns.

Compounds of Formulae 1.1, 1.2, 1.3, 1.5, 1.6, and 1.8, wherein P.G. isbenzyl (Bn) or para-methoxy benzyl (PMB) and R₃ is as originallydefined, and compounds of Formula 1.10, wherein P.G. istriisopropylsilyl (TIPS) and R₃ is as originally defined, can beprepared by the methods shown in Scheme 1, steps a-h. Compounds ofFormula 1.0, wherein Z is ethoxy (—OCH₂CH₃, OEt) or pyrrolidine and P.G.is Bn or PMB, can be treated with a mixture of an organometallicnucleophile, such as cyclopentylmagnesium bromide, and a reducing agent,such as lithium borohydride (LiBH₄), in a polar, aprotic solvent such astetrahydrofuran (THF) at a reduced temperature of about −20° C. to about0° C. to afford compounds of Formulae 1.1 and 1.2, wherein R₃ is aspreviously defined, as shown in a. The alcohol of Formula 1.3, whereinP.G. is Bn, can be prepared from the compound of Formula 1.0, wherein Zis OEt and P.G. is Bn, by treating with lithium aluminum hydride (LAH)in an ethereal solvent, such as diethyl ether (Et₂O), at a temperatureof about 0° C., as shown in b. Additionally, the compound of Formula1.0, wherein Z is OEt and P.G. is Bn or PMB, can be converted to thealdehyde of Formula 1.4 by treating with a catalyst, such aschlorobis(cyclooctene)iridium(I) dimer (Ir₂(coe)₄Cl₂), and a reducingagent, such as diethylsilane (Et₂SiH₂), in a halogenated solvent likedichloromethane (CH₂Cl₂), as described by Cheng, C.; Brookhart, M.Angew. Chem. Int. Ed. 2012, 51, 9422-9424 and shown in c. The compoundsof Formulae 1.5 and 1.6, wherein R₃ is as previously defined, can beobtained by treating the aldehyde of Formula 1.4 with a carbonnucleophile, for example phenyl magnesium bromide or(E)-prop-1-en-1-ylmagnesium bromide, in a polar, aprotic solvent likeTHF at a reduced temperature of about −78° C. to about 23° C., asdepicted in d. A mixture of compounds of Formulae 1.5 and 1.6, whereinR₃ is as previously defined, can be oxidized to give a compound ofFormula 1.7, wherein R₃ is as originally defined, by treating with anoxidant, such as Dess-Martin Periodinane (DMP), in a solvent like CH₂Cl₂at a temperature of about 0° C. to about 23° C., as shown in e.Compounds of Formula 1.8, wherein R₃ is as previously defined, can beprepared by treating compounds of Formula 1.7, wherein R₃ is aspreviously defined, with a reducing agent, such as zinc borohydride,prepared in situ from zinc(II) chloride (ZnCl₂) and sodium borohydride(NaBH₄), in an ethereal solvent like Et₂O at a temperature of about 0°C. to about 23° C., as depicted in f. The compound of Formula 1.0,wherein P.G. is TIPS, can be treated with a reducing agent, such asdiisobutylaluminum hydride (DIBAL), in a halogenated solvent like CH₂Cl₂at a temperature of about −78° C. to about 0° C. to afford the aldehydeof Formula 1.9, as depicted in g. The compound of Formula 1.10 can beprepared from the aldehyde of Formula 1.9 by treating with anucleophile, such as (+)-Ipc₂-allylborane, in an ethereal solvent likeEt₂O at a temperature of about −78° C. to about 0° C., as shown in h.

Compounds of Formula 2.3, wherein R₈ is as originally defined, can beprepared by the method shown in Scheme 2, steps a-b. As depicted in a,compounds of Formula 2.1, wherein R₈ is as originally defined, can beprepared from compounds of Formula 2.0, wherein R₈ is as originallydefined, by treating with an alkoxy borane, such as pinacol borane, inthe presence of a nickel catalyst, such as bis(cyclooctadiene)nickel(0)(Ni(cod)₂), at a temperature of about 0° C. to about 23° C. in anaprotic solvent like toluene, as described by Ely, R. J.; Morken, J. P.J. Am. Chem. Soc. 2010, 132, 2534-2535. Compounds of Formula 2.3,wherein R₈ is as previously defined, can be prepared from compounds ofFormula 2.1, wherein R₈ is as previously defined, by treating with abenzyl (Bn) or p-methoxybenzyl (PMB) protected, lactate-derivedaldehyde, such as a compound of Formula 2.2, as shown in b.

Compounds of Formula 3.2, wherein R₈ is as originally defined, can beprepared by the method shown in Scheme 3, steps a-b. Compounds ofFormula 3.1, wherein R₈ is as originally defined, can be prepared bytreating compounds of Formula 3.0, wherein R₈ is as originally defined,with an alkyllithium reagent, such as sec-butyllithium, followed by analkoxyborane, such as B-methoxydiisopinocampheylborane, in a polar,aprotic solvent like THF at a temperature of about −78° C. to about 23°C., as described by Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am.Chem. Soc. 1988, 110, 1535-1538, and shown in a. Compounds of Formula3.2, wherein R₈ is as previously defined, can be prepared from compoundsof Formula 3.1, wherein R₈ is as previously defined, by treating with aLewis acid, such as borontrifluoride diethyl etherate, followed by a Bnor PMB protected lactate-derived aldehyde, such as a compound of Formula2.2, at a temperature of about −78° C. to about 23° C., as shown in b.

Compounds of Formulae 4.1, 4.2, 4.3, and 4.4, wherein R₃ is asoriginally defined, can be obtained using the methods outlined in Scheme4, steps a-f. Compounds of Formula 4.1, wherein R₃ is as previouslydefined and R₄ is acyl, can be prepared from compounds of Formula 4.0,wherein R₃ is as previously defined, by treating with an acyl halide,such as isobutyryl chloride, in the presence of a base, such astriethylamine (TEA), and an amine catalyst, such asN,N-dimethylaminopyridine (DMAP), in a halogenated solvent like CH₂Cl₂,as shown in a. Compounds of Formula 4.2, wherein R₃ is as previouslydefined and R₄ is aryl, can be prepared by treating solutions ofcompounds of Formula 4.0, wherein R₃ is as previously defined, in asolvent like toluene, with an organometallic species, such asbis(acetate-O)triphenyl-bismuth(V) (Ph₃Bi(OAc)₂), in the presence of acatalyst, such as copper(II) acetate (Cu(OAc)₂), at an elevatedtemperature of about 50° C., as shown in b. Alternatively, arylatedproducts of Formula 4.2, wherein R₃ is as previously defined, can beprepared by treating compounds of Formula 4.0, wherein R₃ is aspreviously defined, with an aryl fluoride, such as 1,3-difluorobenzene,and an alkoxide base, such as potassium tert-butoxide (KOt-Bu), in apolar, aprotic solvent like N,N-dimethyl formamide (DMF) at an elevatedtemperature of about 50° C. to about 70° C., as shown in c. Compounds ofFormula 4.3, wherein R₃ is as previously defined and R₄ is alkyl, can beprepared from compounds of Formula 4.0, wherein R₃ is as previouslydefined, by treating with a base such as KOt-Bu or sodium hydride (NaH)and an electrophile, for example an alkyl halide like(bromomethyl)cyclopropane, in a polar, aprotic solvent like DMF at anelevated temperature of about 50° C., as shown in d. Compounds ofFormula 4.4, wherein R₃ is as previously defined and R₄ is alkenyl, canbe prepared from compounds of Formula 4.0, wherein R₃ is as previouslydefined, by treatment with a base, such as KOt-Bu or NaH, and an allylicelectrophile, such as 3-bromo-2-methylprop-1-ene, in a polar, aproticsolvent like DMF at an elevated temperature of about 50° C., as shown ine. Alternatively, compounds of Formula 4.4, wherein R₃ is as previouslydefined and R₄ is alkenyl, can be prepared from compounds of Formula4.0, by treating with a symmetric or mixed allyl-carbonate, such astert-butyl cyclopent-2-en-1-yl carbonate, in the presence of a palladiumcatalyst, for example tris(dibenzylideneacetone)-dipalladium(0)(Pd₂(dba)₃), and ligand, such as 1,1′-bis(diphenylphosphino)ferrocene(dppf), in a polar, aprotic solvent like THF at an elevated temperatureof about 65° C., as depicted in f.

Compounds of Formula 5.1, wherein R₃ is as originally defined, but notalkenyl, can be prepared according to the method outlined in Scheme 5.Compounds of Formula 5.0, wherein R₃ is as originally defined, but notalkenyl, can be treated with a palladium catalyst liketetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄) and a boronateester or boronic acid, such as phenylboronic acid, in the presence of analkali carbonate base, such as sodium carbonate (Na₂CO₃), in a mixedsolvent system, such as aqueous dioxane, at an elevated temperature ofabout 80° C. to afford compounds of Formula 5.1, wherein R₃ is aspreviously defined, as shown in a.

Compounds of Formulae 6.2, 6.4, and 6.5, wherein Z is methylene (CH₂) orOxygen (O), R₄ and R₈ are as originally defined, but not alkenyl, andR₁₀ is alkyl, can be obtained via the methods outlined in Scheme 6,steps a-f. Compounds of Formula 6.1, wherein Z is CH₂ or O and R₄ and R₈are as originally defined, but not alkenyl, can be prepared fromcompounds of Formula 6.0, wherein Z is CH₂ or O and R₄ and R₈ are asoriginally defined, but not alkenyl, through standard hydroborationconditions, namely by treating with a borane reagent, such as9-borabicyclo[3.3.1]nonane (9-BBN), in a polar, aprotic solvent like THFat about 23° C., and oxidation of the resultant boron intermediate bytreating with sodium hydroxide (NaOH) and hydrogen peroxide (H₂O₂), asshown in a. Compounds of Formula 6.2, wherein Z, R₄, R₈ and R₁₀ are aspreviously defined, can be prepared by treating compounds of Formula6.1, wherein Z, R₄, and R₈ are as previously defined, with anelectrophile, such as trimethyloxonium tetrafluoroborate, in thepresence of a base, such as N,N,N′,N′-tetramethylnaphthalene-1,8-diamine(Proton Sponge®), in a polar, aprotic solvent like CH₂Cl₂ at atemperature of about 0° C. to about 23° C., as shown in b.Alternatively, alcohols of Formula 6.1, wherein Z, R₄, and R₈ are aspreviously defined, can be further functionalized by treating with aprotected aziridine, for example (R)-2-benzyl 1-tert-butylaziridine-1,2-dicarboxylate, in the presence of a lewis acid, such asscandium(III) triflate (Sc(OTf)₃), in an aprotic solvent like CH₂Cl₂ ata temperature of about 0° C. to about 23° C., as shown in c. Compoundsof Formula 6.3, wherein Z is CH₂ or O and R₄ and R₈ are as originallydefined, but not alkenyl, can be prepared by subjecting compounds ofFormula 6.0, wherein Z, R₄, and R₈ are as previously defined, tostandard ozonolysis/reduction conditions, namely treatment with ozone(O₃) in a solvent mixture such as CH₂Cl₂ and methanol (MeOH) at atemperature of about −78° C., followed by the addition of sodiumborohydride (NaBH₄) and MeOH, as shown in d. Compounds of Formula 6.4,wherein Z, R₄, R₈, and R₁₀ are as previously defined, can be preparedfrom compounds of Formula 6.3, wherein Z, R₄, and R₈ are as previouslydefined, by treatment with an electrophile, such as trimethyloxoniumtetrafluoroborate, and a base, such as Proton Sponge®, in an aproticsolvent like CH₂Cl₂ at a temperature of about 0° C. to about 23° C., asshown in e. Cyclopropyl compounds of Formula 6.5, wherein Z, R₄, and R₈are as previously defined, can be prepared by treating etherialsolutions of compounds of Formula 6.0, wherein Z, R₄, and R₈ are aspreviously defined, with a dihalomethane reagent, such as diidomethane,in the presence of diethyl zinc (Et₂Zn) at a temperature of about 0° C.to about 23° C., as shown in f.

Compounds of Formula 7.2, wherein R₄ and R₁₀ are as originally defined,can be prepared according to the methods outlined in Scheme 7, stepsa-b. Compounds of Formula 7.0, wherein R₄ is as originally defined, canbe subjected to the ozonolysis conditions described in Scheme 6, step d,to afford compounds of Formula 7.1, wherein R₄ is as originally defined,as shown in a. Compounds of Formula 7.2, wherein R₄ is as originallydefined and R₁₀ is alkyl, can be prepared from compounds of Formula 7.1,wherein R₄ is as previously defined, by treating with a base, such asNaH, in a polar, aprotic solvent like DMF at a temperature of about 0°C. to about 23° C. and quenching the resultant alkoxide with anelectrophile, such as propyl 4-methylbenzenesulfonate, as shown in b.Additionally, compounds of Formula 7.2, wherein R₄ is as originallydefined and R₁₀ is aryl, can be prepared from alcohols of Formula 7.1,wherein R₄ is as previously defined, using the arylation conditionsdescribed in Scheme 4, step b, as shown in c.

Compounds of Formula 8.3, wherein R₃ and R₄ are as originally defined,can be prepared according to the methods outlined in Scheme 8, stepsa-d. Compounds of Formula 8.3, wherein R₃ and R₄ are as previouslydefined, but not alkenyl, can be prepared by treating compounds ofFormula 8.0, wherein R₃ and R₄ are originally defined, with a catalyst,such as palladium on carbon (Pd/C), in the presence of hydrogen gas (H₂)in a polar solvent like ethyl acetate (EtOAc) or MeOH or with analternate source of hydrogen, such as cyclohexene, in a polar solventlike EtOH, as shown in a. Additionally, compounds of Formula 8.0,wherein R₃ is as previously defined and R₄ is an aryl chloride, can besubjected to modified hydrogenolysis conditions, namely exposing an EtOHsolution of the aryl chloride to H₂ in the presence of Pd/C and NEt₃ toafford compounds of Formula 8.3, wherein R₃ and R₄ are as originallydefined, but R₃ is not alkenyl, as shown in b. Compounds of Formula 8.3,wherein R₃ and R₄ are as originally defined, can be obtained by treatingcompounds of Formula 8.1, wherein R₃ and R₄ are as originally defined,with an oxidant, such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ), in a solvent mixture like aqueous CH₂Cl₂, as indicated in c.Compounds of Formula 8.3, wherein R₃ and R₄ are as originally defined,may also be prepared by treating compounds of Formula 8.2, wherein R₃and R₄ are as originally defined, with a fluoride source, such astetra-N-butyl ammonium fluoride (TBAF), in a solvent like THF at atemperature of about 0° C. to about 23° C., as depicted in d.

Compounds of Formula 9.3, wherein R₃ is as originally defined, but notalkenyl, can be prepared according to the methods outlined in Scheme 9,steps a-c. As depicted in a, the compound of Formula 9.0 can be treatedwith a reducing agent, such as LiBH₄, and a carbon nucleophile, forexample a Grignard reagent like i-propyl magnesium chloride, in a polar,aprotic solvent like THF at a temperature of about −10° C. to about 0°C. to afford compounds of Formula 9.1, wherein R₃ is as originallydefined. Compounds of Formula 9.2, wherein R₃ is as originally defined,can be prepared from compounds of Formula 9.1, wherein R₃ is aspreviously defined, by treating with a base, such as KOt-Bu, andquenching the resultant alkoxide anion with an electrophile, such as1-chloro-3-fluorobenzene, in a polar, aprotic solvent like DMF, as shownin b. Compounds of Formula 9.3, wherein R₃ is as previously defined, canbe prepared from compounds of Formula 9.2, wherein R₃ is as previouslydefined, using the methodology described in Scheme 8, step b, as shownin c.

Compounds of Formula 10.2 and 10.3, wherein R₂ and R₃ are as originallydefined, can be prepared using the methods described in Scheme 10, stepsa-d. Compounds of Formula 9.3, wherein R₃ is as originally defined, canbe treated with an aqueous acid solution, such as 1 normal (N) hydrogenchloride (HCl), to afford diols of Formula 10.0, wherein R₃ is asoriginally defined, as depicted in a. Compounds of Formula 10.1, whereinR₃ is as originally defined, can be prepared from compounds of Formula10.0, wherein R₃ is as previously defined, by treating with an oxidant,such as sodium periodate (NaIO₄), in a halogenated solvent like CH₂Cl₂at a temperature of about 23° C., as shown in b. Aldehydes of Formula10.1, wherein R₃ is as previously defined, can be treated with areducing agent, such as NaBH₄, in a solvent like MeOH at a temperatureof about 23° C. to afford alcohols of Formula 10.2, wherein R₂ and R₁₂are hydrogen and R₃ is as previously defined, as shown in c.Additionally, aldehydes of Formula 10.1, wherein R₃ is as previouslydefined, can be treated with a carbon nucleophile, for example aGrignard reagent like ethyl magnesium bromide (EtMgBr), in a polar,aprotic solvent like THF at a temperature of about −78° C. to affordcompounds of Formula 10.3, wherein R₂ and R₃ are as originally definedand R₁₂ is hydrogen, as depicted in d.

Compounds of Formula 11.2, wherein R₂, R₃, and R₁₂ are as originallydefined, can be prepared according to the methods outlined in Scheme 11,steps a-c. As shown in a, acetals of Formula 9.3, wherein R₃ is asoriginally defined, can be treated with an oxidant, such asorthoperiodic acid, in a mixed solvent system, such as acetonitrile(CH₃CN), carbon tetrachloride (CCl₄), and water (H₂O), followed by asecond oxidant, such as ruthenium trichloride (RuCl₃), to affordcarboxylic acids of Formula 11.0, wherein R₃ is as originally defined.Compounds of Formula 11.0, wherein R₃ is as previously defined, can betreated with trimethylsilyl diazomethane in a solvent mixture like THF,benzene, and MeOH to afford esters of Formula 11.1, wherein R₃ is asoriginally defined, as shown in b. Compounds of Formula 11.2, whereinR₂, R₃, and R₁₂ are as previously defined, can be prepared from estersof Formula 11.1, wherein R₃ is as previously defined, by treating with acarbon nucleophile, for example a Grignard reagent like methyl magnesiumbromide (MeMgBr) in a mixture of ethereal solvents, such as THF andEt₂O, at a temperature of about 0° C. to about 23° C., as shown in c.

Compounds of Formula 12.2, wherein R₁, R₂, R₃, R₄, R₁₁, and R₁₂, are asoriginally defined, can be prepared according to the method outlined inScheme 12. Alcohols of Formula 12.0, wherein R₂, R₃, R₄, and R₁₂, are asoriginally defined, can be treated with compounds of Formula 12.1,wherein R₁ and R₁₁ are as originally defined, a coupling reagent, suchas 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine hydrochloride(EDC) or a polymer-supported carbodiimide (PS-CDI), and a catalyst, suchas DMAP, in a halogenated solvent like CH₂Cl₂ to afford compounds ofFormula 12.2, wherein R₁, R₂, R₃, R₄, R₁₁, and R₁₂ are as previouslydefined, as shown in a.

Compounds of Formula 13.3, wherein R₁, R₄, and R₁₁ are as originallydefined and R₈ is alkyl, can be prepared according to the methodsoutlined in Scheme 13, steps a-c. As depicted in a, compounds of Formula13.1, wherein R₁, R₄, and R₁₁ are as originally defined, can be preparedby treating compounds of Formula 13.0, wherein R₁, R₄, and R₁₁ are asoriginally defined, with di-tert-butyl dicarbonate (BOC₂O) and DMAP inan aprotic solvent like CH₃CN at about 23° C. Compounds of Formula 13.2,wherein R₁, R₄, and R₁₁ are as originally defined, can be prepared fromcompounds of Formula 13.1, wherein R₁, R₄, and R₁₁ are as previouslydefined, using the ozonolysis conditions described in Scheme 6, step d,as shown in b. Compounds of Formula 13.3, wherein R₁, R₄, R₈, and R₁₁are as previously defined, can be prepared from compounds of Formula13.2, wherein R₁, R₄, and R₁₁ are as previously defined, using themethodology described in Scheme 6, step b, as shown in c.

Compounds of Formula 14.7, wherein R₁, R₂, R₃, R₄, R₆, R₁₁, and R₁₂ areas originally defined, can be prepared according to the methods outlinedin Scheme 14, steps a-e. Compounds of Formula 14.0, wherein R₁, R₂, R₃,R₄, R₁₁, and R₁₂ are as originally defined, but not alkenyl, can betreated with an acid, such as a 4 N solution of HCl in dioxane, in ahalogenated solvent like CH₂Cl₂ to afford compounds of Formula 14.2,wherein R₁, R₂, R₃, R₄, R₁₁, and R₁₂, are as originally defined, but notalkenyl, as shown in a. Compounds of Formula 14.3, wherein R₁, R₂, R₃,R₄, R₁₁, and R₁₂ are as originally defined, can be prepared by treatingcompounds of Formula 14.0, wherein R₁, R₂, R₃, R₄, R₁₁, and R₁₂ are asoriginally defined, with an acid, such as 2,2,2-trifluoroacetic acid, ina halogenated solvent like CH₂Cl₂, as shown in b. Compounds of Formula14.4, wherein R₁, R₂, R₃, R₄, R₁₁, and R₁₂ are as originally defined,can be prepared by treating compounds of Formula 14.0, wherein R₁, R₂,R₃, R₄, R₁₁, and R₁₂ are as originally defined, with a reagent such astrimethylsilyl trifluoromethansulfonate (TMSOTf) and an amine base, suchas 2,6-lutidine, in a halogenated solvent like CH₂Cl₂, as shown in c.Compounds of Formula 14.5, wherein R₁, R₂, R₃, R₄, R₁₁, and R₁₂ are aspreviously defined, can be prepared by treating compounds of Formula14.1, wherein R₁, R₂, R₃, R₄, R₁₁, and R₁₂ are as originally defined,with an amine base, such as morpholine, in a polar, aprotic solvent likeTHF, as shown in d. Compounds of Formulae 14.2, 14.3, 14.4, and 14.5,wherein R₁, R₂, R₃, R₄, R₁₁, and R₁₂ are as originally defined, can betreated with compounds of Formula 14.6, wherein R₆ is as originallydefined, in the presence of a base, such as diisopropylethylamine, and apeptide coupling reagent, such asbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) or O-(7-azabenzo-triazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), in an halogenated solvent like CH₂Cl₂, toafford compounds of Formula 14.7, wherein R₁, R₂, R₃, R₄, R₆, R₁₁, andR₁₂ are as previously defined, as shown in e.

Compounds of Formula 15.1, wherein R₁, R₂, R₃, R₆, R₁₁, and R₁₂ are asoriginally defined, but not alkenyl, and R₈ is as originally defined,but not alkenyl or chloro, can be prepared according to the methodoutlined in Scheme 15. Compounds of Formula 15.0, wherein R₁, R₂, R₃,R₆, R₈, R₁₁, and R₁₂ are as originally defined, can be subjected to thehydrogenation conditions described in Scheme 8, step b to affordcompounds of Formula 15.1, wherein R₁, R₂, R₃, R₆, R₈, R₁₁, and R₁₂ areas defined above, as depicted in a.

Compounds of Formula 16.1, wherein R₁, R₂, R₃, R₄, R₆, R₇, R₁₁, and R₁₂are as originally defined, can be prepared according to the methodoutlined in Scheme 16. Compounds of Formula 16.0, wherein R₁, R₂, R₃,R₄, R₆, R₁₁, and R₁₂ are as previously defined, can be treated with anappropriate alkyl halide with or without a reagent such as sodium iodide(NaI) and an alkali carbonate base, such as Na₂CO₃ or potassiumcarbonate (K₂CO₃), in a solvent like acetone or by treatment with anacyl halide in the presence of an amine base, such as pyridine, NEt₃,DMAP, or mixtures thereof, in an aprotic solvent such as CH₂Cl₂, toafford compounds of Formula 16.1, wherein R₁, R₂, R₃, R₄, R₆, R₇, R₁₁,and R₁₂ are as previously defined, as shown in a.

EXAMPLES Example 1A: Preparation of(2S,3R)-2-(benzyloxy)-4-ethylhexan-3-ol and(2S,3S)-2-(benzyloxy)-4-ethylhexan-3-ol

To a solution of pentan-3-ylmagnesium bromide (77.0 milliliters (mL),154 millimoles (mmol)) and lithium borohydride (LiBH₄; 49.9 mL, 100mmol, 2 molar (M) in THF) in THF (400 mL) at −5° C. was added neat(S)-ethyl 2-(benzyloxy)propanoate (16.0 grams (g), 77.0 mmol) dropwisevia syringe pump addition over approximately a 1 hour (h) period, at arate which maintained the internal temperature below −3° C. The reactionvessel was allowed to slowly warm to room temperature overnight, and thereaction mixture was quenched by slowly adding the mixture to water(H₂O, 300 mL) over a 30 minute (min) period. The mixture was dilutedwith diethyl ether (Et₂O; 300 mL), the phases were separated, and theaqueous (aq.) phase was extracted with Et₂O (2×100 mL). The combinedorganic phases were washed with saturated (sat.) aq. sodium chloride(NaCl, brine; 300 mL), dried over magnesium sulfate (MgSO₄), filtered,and concentrated. The resulting oil was purified by flash columnchromatography (silica gel (SiO₂), 0→15% ethyl acetate (EtOAc) inhexanes) to afford the title compounds (9.61 g, 53% and 3.46 g, 19%,respectively) as colorless oils:

major: IR (Thin film) 3471, 3031, 2962, 2932, 2874, 1454, 1382 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.38-7.26 (m, 5H), 4.60 (d, J=11.8 Hz, 1H), 4.51(d, J=11.8 Hz, 1H), 3.68 (ddd, J=7.4, 3.6, 2.7 Hz, 1H), 3.63 (qd, J=6.2,3.7 Hz, 1H), 2.05 (d, J=2.8 Hz, 1H), 1.65 (dq, J=9.9, 7.4 Hz, 1H),1.44-1.34 (m, 2H), 1.36-1.18 (m, 2H), 1.18 (d, J=6.2 Hz, 3H), 0.88 (t,J=7.3 Hz, 3H), 0.84 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ138.53, 128.41, 127.63, 127.60, 75.65, 73.56, 70.50, 41.34, 20.59,20.51, 13.13, 10.44, 10.29;

minor: IR (Thin film) 3472, 3031, 2961, 2932, 2874, 1497, 1454, 1376cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.32 (m, 4H), 7.32-7.26 (m, 1H),4.68 (d, J=11.3 Hz, 1H), 4.44 (d, J=11.4 Hz, 1H), 3.66-3.54 (m, 1H),3.43 (dt, J=6.8, 3.8 Hz, 1H), 2.43 (dd, J=4.0, 0.8 Hz, 1H), 1.54-1.36(m, 3H), 1.36-1.23 (m, 2H), 1.19 (d, J=6.1 Hz, 3H), 0.90 (t, J=7.4 Hz,3H), 0.89 (t, J=7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 138.40, 128.46,127.79, 127.73, 76.67, 76.07, 70.99, 42.65, 22.73, 20.79, 15.78, 11.98,11.65.

Example 1B, Step 1: Preparation of (S)-2-((4-methoxybenzyl)oxy)propanal

To a solution of(S)-ethyl 2-((4-methoxybenzyl)oxy)propanoate (5.00 g,21.0 mmol) in CH₂Cl₂ (30 mL) at 0° C. was addedchlorobis(cyclooctene)iridium(I) dimer (Ir₂Cl₂(coe)₄; 94.0 milligrams(mg), 0.105 mmol) followed by diethylsilane (Et₂SiH₂; 4.08 mL, 31.5mmol) over a 10 min period. The mixture was stirred at 0° C. for 30 min,warmed to room temperature and stirred for 3 h, cooled to 0° C., andquenched by adding 1 normal (N) aq. hydrogen chloride (HCl; 12 mL). Theresulting solution was warmed to room temperature and stirred for 15min. The phases were separated and the aq. phase was extracted withCH₂Cl₂ (3×30 mL). The combined organic phases were washed with brine,dried over sodium sulfate (Na₂SO₄), filtered, evaporated, and purifiedby flash column chromatography (SiO₂, 2→50% acetone in hexanes) toafford the title compound (4.27 g, 100%) as a yellow oil: IR (Thin film)2934, 2837, 2865, 1731, 1512 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 9.64 (d,J=1.9 Hz, 1H), 7.35-7.21 (m, 2H), 6.95-6.79 (m, 2H), 4.63-4.40 (m, 2H),3.94-3.76 (m, 1H), 3.81 (s, 3H), 1.31 (d, J=6.9 Hz, 3H); ¹³C NMR (101MHz, CDCl₃) δ 203.58, 159.54, 129.65, 129.37, 113.98, 79.14, 71.75,55.30, 15.34.

Example 1B, Step 2: Preparation of(1S,2S)-2-((4-methoxybenzyl)oxy)-1-phenylpropan-1-ol

To a solution of (S)-2-((4-methoxybenzyl)oxy)propanal (3.38 g, 17.4mmol) in Et₂O (58 mL) at −78° C. was added phenylmagnesium bromide (34.8mL, 34.8 mmol, 1 M in THF) dropwise, and the reaction mixture wasallowed to warm to room temperature, stirred overnight, and quenched bythe addition of sat. aq. ammonium chloride (NH₄Cl). The mixture waspartitioned between H₂O and EtOAc, the phases were separated, and theaq. phase was extracted with EtOAc (2×). The combined organic phaseswere washed with brine, dried over Na₂SO₄, filtered, evaporated, andpurified by flash column chromatography (SiO₂, 2→50% acetone in hexanes)to afford an inseparable mixture of diastereomers (d.r. 3:1 SS:RS) ofthe title compound (3.29 g, 66%) as a yellow oil: ¹H NMR (400 MHz,CDCl₃; major) δ 7.37-7.25 (m, 7H), 6.89 (d, J=8.6 Hz, 2H), 4.62 (d,J=11.0 Hz, 1H), 4.44 (dd, J=7.8, 2.1 Hz, 1H), 4.41 (d, J=11.0 Hz, 1H),3.82 (s, 3H), 3.60 (dq, J=7.8, 6.2 Hz, 1H), 3.21 (d, J=2.1 Hz, 1H), 1.05(d, J=6.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 159.34, 140.56, 130.21,129.46, 128.31, 127.25, 126.31, 113.93, 79.66, 78.32, 70.92, 55.30,15.56; ESIMS m/z 295 (([M+Na]⁺)).

Example 1B, Step 3: Preparation of (S,E)-2-(benzyloxy)hex-4-en-3-one

To a solution of (2S)-2-(benzyloxy)hex-4-en-3-ol (1.3 g, 6.30 mmol) andsodium bicarbonate (NaHCO₃; 0.582 g, 6.93 mmol) in CH₂Cl₂ (25.2 mL) at0° C. was added Dess-Martin Periodinane (DMP; 2.94 g, 6.93 mmol), andthe reaction mixture was removed from the cold bath, stirred at roomtemperature for 6 h, and quenched by the addition of sat. aq. sodiumthiosulfate (Na₂S₂O₃; 10 mL). The mixture was diluted with CH₂Cl₂ (10mL) and the biphasic solution was stirred vigorously for 15 min, dilutedwith H₂O (10 mL), and the phases were separated. The aq. phase wasextracted with CH₂Cl₂ (2×15 mL) and the combined organic phases werewashed successively with sat. aq. NaHCO₃ (10 mL), H₂O (20 mL), and brine(20 mL), dried over Na₂SO₄, filtered, and concentrated. The cruderesidue was purified by flash column chromatography (SiO₂, 0→50% EtOAcin hexanes) to afford the title compound (480 mg, 37%) and(S,Z)-2-((4-methoxybenzyl)oxy)hex-4-en-3-one, the latter of which wasdissolved in CH₂Cl₂ (5 mL) and stirred in the presence of DABCO (10 mg)for 18 h to afford additional title compound (400 mg, 31%): ¹H NMR (400MHz, CDCl₃) δ 7.40-7.26 (m, 5H), 7.08 (dq, J=15.6, 6.9 Hz, 1H), 6.55(dq, J=15.6, 1.7 Hz, 1H), 4.57 (d, J=11.7 Hz, 1H), 4.43 (d, J=11.7 Hz,1H), 4.05 (q, J=6.9 Hz, 1H), 1.93 (dd, J=6.9, 1.7 Hz, 3H), 1.36 (d,J=6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 201.11, 144.70, 137.66,128.45, 127.84, 126.07, 80.00, 71.76, 18.56, 18.00; ESIMS m/z 205(([M+H]⁺)).

Example 1B, Step 4: Preparation of (2S,3R,E)-2-(benzyloxy)hex-4-en-3-ol

To a solution of NaBH₄ (445 mg, 11.8 mmol) in Et₂O (15.7 mL) at 0° C.was added zinc(II) chloride (ZnCl₂; 5.90 mL, 5.87 mmol, 1 M in Et₂O),and the mixture was removed from the cold bath and stirred at roomtemperature for 18 h. The reaction mixture was cooled to 0° C., treateddropwise with a solution of (S,E)-2-(benzyloxy)hex-4-en-3-one (800 mg,3.92 mmol) in Et₂O (2 mL) and stirred for 2 h. The reaction mixture waswarmed to room temperature, stirred at room temperature for 3 h, dilutedwith THF (5 mL) and stirring continued for an additional 1 h, and thenquenched by the careful addition of sat. aq. NH₄Cl (25 mL). The phaseswere separated and the aq. phase was extracted with Et₂O (3×20 mL). Thecombined organic phases were washed with brine (10 mL), dried overNa₂SO₄, filtered, evaporated, and the crude residue was purified byflash column chromatography (SiO₂, 0→35% EtOAc in hexanes) to afford thetitle compound (620 mg, 77%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃)δ 7.38-7.24 (m, 5H), 5.80-5.66 (m, 1H), 5.55-5.43 (m, 1H), 4.63 (d,J=11.8 Hz, 1H), 4.53 (d, J=11.8 Hz, 1H), 4.20-4.12 (m, 1H), 3.57 (qd,J=6.4, 3.4 Hz, 1H), 2.28-2.22 (m, 1H), 1.75-1.68 (m, 3H), 1.14 (d, J=6.3Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 138.54, 129.43, 128.68, 128.42,127.64, 77.76, 74.62, 70.86, 17.91, 14.20; ESIMS m/z 229 (([M+Na]⁺)).

Example 1C, Step 1: Preparation of(S)-2-((triisopropylsilyl)oxy)propanal

To a solution of(S)-ethyl 2-((triisopropylsilyl)oxy)propanoate (20.5 g,74.7 mmol) in CH₂Cl₂ (373 mL) at −78° C. was added a solution ofdiisopropylaluminum hydride (DIBAL; 149 mL, 149 mmol, 1 M in CH₂Cl₂)over 4 h, and the reaction mixture was stirred at −78° C. for anadditional 30 min, quenched with EtOAc (75 mL), and warmed to 0° C. Theheterogeneous mixture was treated with aq. sodium tartrate (˜200 mL) andthe mixture was warmed to room temperature and stirred vigorouslyovernight. The phases were separated and the aq. phase was extractedwith CH₂Cl₂ (2×150 mL). The combined organic phases were dried overNa₂SO₄, filtered, and concentrated to an oil, which was purified byflash column chromatography (SiO₂, 0→10% EtOAc in hexanes) to afford thetitle compound (12.64 g, 70%) as a clear, colorless oil: ¹H NMR (400MHz, CDCl₃) δ 9.66 (d, J=1.7 Hz, 1H), 4.18 (qd, J=6.8, 1.7 Hz, 1H), 1.31(d, J=6.8 Hz, 3H), 1.07 (td, J=5.6, 5.0, 3.2 Hz, 21H); ¹³C NMR (101 MHz,CDCl₃) δ 204.58, 73.82, 18.95, 17.89, 12.14; EIMS m/z 187 [M-i-Pr]⁺.

Example 1C, Step 2: Preparation of(2S,3R)-2-((triisopropylsilyl)oxy)hex-5-en-3-ol

To a solution of (+)-Ipc₂-allylborane (25.0 mL, 25.0 mmol, 1 M inpentane) in Et₂O (100 mL) at −78° C. was added a solution of(S)-2-((triisopropylsilyl)oxy)propanal (4.61 g, 20.0 mmol) in Et₂O (60mL) over 1.5 h, and the reaction mixture was stirred at −78° C. for anadditional 1.5 h, treated with MeOH (50 mL), and stirred for 5 min. Themixture was treated with pH 7 buffer (70 mL), warmed to 0° C., andtreated with 30% aq. H₂O₂ (60 mL). The reaction mixture was stirred at0° C. for 2.5 h, allowed to slowly warm to room temperature, and stirredfor 30 h. The phases were separated and the aq. phase was extracted withEt₂O (3×100 mL). The combined organic phases were dried over MgSO₄,filtered, and concentrated to a clear oil, which was purified by flashcolumn chromatography (SiO₂, 0→15% EtOAc in hexanes) to afford the titlecompound (5.00 g, 87%) as a clear, slightly rose-colored oil: IR (neat)3480, 2943, 2866, 1463, 1067, 881 cm; ¹H NMR (400 MHz, CDCl₃) δ 5.85(ddt, J=17.2, 10.2, 7.0 Hz, 1H), 5.22-4.97 (m, 2H), 3.93 (qd, J=6.2, 3.3Hz, 1H), 3.70 (ddt, J=8.3, 5.7, 2.9 Hz, 1H), 2.34 (d, J=2.6 Hz, 1H),2.30-2.09 (m, 2H), 1.14 (d, J=6.3 Hz, 3H), 1.12-1.03 (m, 21H); HRMS-ESI(m/z) ([M+H]⁺) calcd for C₁₅H₃₃O₂Si, 274.2270; found, 274.2274.

Example 1D: Preparation of (S)-2-(benzyloxy)propan-1-ol

To a solution of LAH (48.0 ml, 24.0 mmol, 0.5M in Et₂O) at 0° C. wasadded (S)-ethyl 2-(benzyloxy)propanoate (5.00 g, 24.0 mmol) dropwiseover a 10 min period, and the reaction mixture was stirred at 0° C. for3 h, quenched slowly by the successive addition of H₂O (900 μL), 1N NaOH(900 μL), and water (2.7 mL). The resulting slurry was stirred for 10min at room temperature, treated with Na₂SO₄, and the mixture wasfiltered through Celite®. The filtrate was concentrated to provide thetitle compound (4.00 g, 24.1 mmol, 100%) as a colorless oil: ¹H NMR (400MHz, CDCl₃) δ 7.41-7.26 (m, 5H), 4.65 (d, J=11.6 Hz, 1H), 4.48 (d,J=11.6 Hz, 1H), 3.74-3.56 (m, 2H), 3.49 (ddd, J=11.5, 7.0, 4.6 Hz, 1H),2.21 (dd, J=7.9, 4.6 Hz, 1H), 1.17 (d, J=6.2 Hz, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 138.46, 128.48, 127.75, 127.73, 75.57, 70.82, 66.36, 15.89;EIMS m/z 166.

Example 1E: Preparation of(1S,2S)-2-((4-methoxybenzyl)oxy)-1-(thiophen-2-yl)propan-1-ol and(1R,2S)-2-((4-methoxybenzyl)oxy)-1-(thiophen-2-yl)propan-1-ol

To a solution of thiophen-2-yllithium (4.00 mL, 4.00 mmol, 1 M in THF)and lithium borohydride (LiBH₄; 1.30 mL, 2.60 mmol, 2 M in THF) in THF(10 mL) at −10° C. was added neat(S)-2-((4-methoxybenzyl)oxy)-1-(pyrrolidin-1-yl)propan-1-one (0.527 g,2.00 mmol) (for preparation see: Pellicena, M.; Solsona, J. G.; Romea,P.; Urpi, F. Tetrahedron 2012, 68, 10338.) dropwise via syringe pumpaddition over approximately a 1 h period, at a rate which maintained theinternal temperature below −5° C. The reaction vessel was allowed toslowly warm to room temperature overnight, and the reaction mixture wasquenched by the addition of sat. aq. NH₄Cl. The aq. phase was extractedwith Et₂O (3×). The combined organic phases were washed with brine,dried over Na₂SO₄, filtered, evaporated, and purified by flash columnchromatography (SiO₂, 2→10% acetone in hexanes) to afford the titlecompounds (0.231 g, 41% and 0.175 g, 31%, respectively) as colorlessoils:

major: ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.21 (m, 3H), 7.05-6.93 (m, 2H),6.94-6.83 (m, 2H), 5.03 (t, J=4.2 Hz, 1H), 4.61 (d, J=11.4 Hz, 1H), 4.48(d, J=11.3 Hz, 1H), 3.81 (s, 3H), 3.88-3.73 (m, 1H), 2.59 (d, J=4.4 Hz,1H), 1.13 (d, J=6.3 Hz, 3H); ESIMS m/z 579 ([2M+Na]⁺).

minor: ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.22 (m, 3H), 7.06-6.92 (m, 2H),6.95-6.84 (m, 2H), 4.73 (dd, J=7.3, 2.7 Hz, 1H), 4.63 (d, J=10.9 Hz,1H), 4.44 (d, J=11.0 Hz, 1H), 3.82 (s, 3H), 3.67 (dq, J=7.3, 6.2 Hz,1H), 3.29 (d, J=2.8 Hz, 1H), 1.14 (d, J=6.1 Hz, 3H); ESIMS m/z 579([2M+Na]⁺).

Example 2: Preparation of (2S,3R,4S)-4-benzyl-2-(benzyloxy)hex-5-en-3-ol

To a round-bottom flask were added bis(cyclooctadiene)nickel(0)(Ni(cod)₂; 0.168 g, 0.609 mmol) and tricyclohexylphosphine (P(C₆H₁₁)₃;0.213 g, 0.761 mmol) under an inert atmosphere (nitrogen gas (N₂) glovebag), and the flask was capped and removed from the bag. The mixture wasdiluted with toluene (22 mL) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane(6.63 mL, 45.7 mmol) was added at room temperature. The reaction mixturewas cooled to 0° C. in an ice bath and treated with neat(E)-buta-1,3-dien-1-ylbenzene (4.76 g, 36.5 mmol) dropwise over a 10 minperiod. The mixture was removed from the ice bath and stirred at roomtemperature for 2 h, cooled to −78° C. in a dry ice/acetone bath, andtreated with (S)-2-(benzyloxy)propanal (5.00 g, 30.5 mmol) followed byBF₃.OEt₂ (0.376 mL, 3.05 mmol). The reaction mixture was allowed toslowly warm to room temperature overnight and quenched by treating withMeOH (5 mL). After stirring for 30 min, the reaction mixture wasconcentrated and purified by flash column chromatography (SiO₂, 0→50%EtOAc in hexanes) to afford the title compound (8.95 g, 99%) as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.30 (m, 3H), 7.32-7.25(m, 1H), 7.25-7.21 (m, 2H), 7.20-7.11 (m, 4H), 5.45 (ddd, J=17.2, 10.3,9.5 Hz, 1H), 4.93 (dd, J=10.3, 1.8 Hz, 1H), 4.79 (ddd, J=17.2, 1.9, 0.7Hz, 1H), 4.55 (d, J=11.7 Hz, 1H), 4.46 (d, J=11.7 Hz, 1H), 3.76 (ddd,J=9.2, 3.2, 2.2 Hz, 1H), 3.56 (qd, J=6.3, 3.1 Hz, 1H), 3.19 (dd, J=13.3,3.5 Hz, 1H), 2.58 (dd, J=13.4, 9.3 Hz, 1H), 2.39 (dt, J=9.2, 3.4 Hz,1H), 2.37 (d, J=2.3 Hz, 1H), 1.17 (d, J=6.3 Hz, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 139.92, 138.48, 137.37, 129.81, 128.46, 127.94, 127.70, 127.66,125.76, 117.21, 76.22, 73.78, 70.56, 48.44, 37.63, 12.21; ESIMS m/z 319(([M+Na]⁺)).

Example 3: Preparation of(2S,3S,4S)-2-(benzyloxy)-4-phenoxyhex-5-en-3-ol

To a solution of 3-propoxyprop-1-ene (5.77 g, 57.6 mmol) in THF (87 mL)at −78° C. was slowly added a solution of sec-butyllithium (s-BuLi; 37.4mL, 52.4 mmol, 1.4 M in cyclohexane), and the resulting solution wasstirred for 40 min at −78° C., treated withmethoxybis((2S,3R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)borane(16.57 g, 52.4 mmol), and stirred at −78° C. for an additional 2.5 h.The reaction mixture was warmed to 0° C. and quenched at 0° C. by theslow addition of aq. 1 N sodium hydroxide (NaOH; 63 mL) followed by 30%aq. hydrogen peroxide (H₂O₂; 21 mL). The resulting mixture was warmed toroom temperature and stirred overnight. The phases were separated andthe aq. phase was extracted with Et₂O (3×), and the combined organicextracts were washed with H₂O and brine, dried over Na₂SO₄, filtered,and evaporated. The resulting crude oil was purified by Kugelrhordistillation (Temperature (T)=60° C., 0.4-0.6 millimeters (mm) Hg) toafford the title compound (10.6 g, 77%) as a slightly yellow oil: ¹H NMR(400 MHz, CDCl₃) δ 7.37-7.33 (m, 4H), 7.32-7.26 (m, 1H), 5.76 (ddd,J=17.2, 10.4, 7.5 Hz, 1H), 5.28 (ddd, J=8.9, 1.8, 0.9 Hz, 1H), 5.28-5.22(m, 1H), 4.61 (d, J=11.6 Hz, 1H), 4.48 (d, J=11.7 Hz, 1H), 3.83 (ddt,J=7.5, 4.5, 0.9 Hz, 1H), 3.58 (p, J=6.1 Hz, 1H), 3.53-3.43 (m, 2H), 3.18(dt, J=9.1, 6.6 Hz, 1H), 2.42 (d, J=5.8 Hz, 1H), 1.62-1.45 (m, 2H), 1.27(d, J=6.2 Hz, 3H), 0.90 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ138.59, 135.88, 128.34, 127.77, 127.54, 118.33, 80.16, 76.18, 74.70,70.69, 70.47, 23.01, 15.25, 10.70; HRMS-ESI (m/z) ([M+H]⁺) calcd forC₁₆H₂₅O₃, 265.1798; found, 265.1793.

Example 4A: Preparation of (S)-2-(benzyloxy)propyl isobutyrate

To a solution of (S)-2-(benzyloxy)propan-1-ol (500 mg, 3.01 mmol) inanhydrous CH₂Cl₂ (10 mL) were added triethylamine (NEt₃; 839 microliters(μL), 6.02 mmol), DMAP (36.7 mg, 0.301 mmol), and isobutyryl chloride(473 μL, 4.51 mmol), and the resulting solution was stirred overnight atroom temperature. The reaction mixture was poured into aq. 1 N HCl (20mL), the phases were separated, and the aq. phase was extracted withCH₂Cl₂ (2×20 mL). The organic extracts were combined, dried over Na₂SO₄,filtered, and evaporated to give a yellow oil which was purified byflash column chromatography (SiO₂, 0→20% acetone in hexanes) to affordthe title compound (687 mg, 97%) as a clear, colorless oil: ¹H NMR (400MHz, CDCl₃) δ 7.37-7.26 (m, 5H), 4.61 (d, J=11.9 Hz, 1H), 4.58 (d,J=11.9 Hz, 1H), 4.18-4.04 (m, 2H), 3.76 (pd, J=6.3, 4.6 Hz, 1H), 2.58(p, J=7.0 Hz, 1H), 1.22 (d, J=6.3 Hz, 3H), 1.19 (d, J=2.3 Hz, 3H), 1.17(d, J=2.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 176.98, 138.51, 128.37,127.60, 127.58, 72.71, 71.04, 67.16, 34.00, 19.01, 18.99, 16.99; ESIMSm/z 237 (([M+H]⁺)).

Example 4B: Preparation of1-((2S,3R,4S)-4-(benzyloxy)-3-phenoxy-2-vinylpentyl)-4-fluorobenzene

To a solution of(2S,3R,4S)-2-(benzyloxy)-4-(4-fluorobenzyl)hex-5-en-3-ol (3 g, 9.54mmol) in anhydrous toluene (48 mL) were addedN-cyclohexyl-N-methylcyclohexanamine (3.04 mL, 14.3 mmol), Ph₃Bi(OAc)₂(7.73 g, 14.3 mmol), and diacetoxycopper (Cu(OAc)₂; 0.347 g, 1.91 mmol).The resulting blue suspension was heated to and stirred at 50° C. for 15h, cooled to room temperature, filtered through a plug of Celite®, andevaporated. The resulting crude material was purified by flash columnchromatography (SiO₂, 1→5% EtOAc in hexanes) to give the title compound(2.77 g, 74%) as a clear, colorless oil: ¹H NMR (400 MHz, CDCl₃) δ7.38-7.18 (m, 7H), 7.09-6.99 (m, 2H), 6.99-6.84 (m, 5H), 5.62 (dt,J=17.2, 9.7 Hz, 1H), 4.96 (dd, J=10.3, 1.7 Hz, 1H), 4.83 (d, J=17.2 Hz,1H), 4.61 (d, J=11.6 Hz, 1H), 4.44 (d, J=11.6 Hz, 1H), 4.32 (t, J=5.5Hz, 1H), 3.82 (p, J=6.1 Hz, 1H), 3.09 (dd, J=13.5, 4.1 Hz, 1H), 2.71(dt, J=9.7, 5.0 Hz, 1H), 2.57 (dd, J=13.3, 9.8 Hz, 1H), 1.27 (d, J=6.2Hz, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 162.06, 160.45, 159.51, 138.48,138.05, 135.87, 135.85, 130.84, 130.79, 129.44, 128.35, 127.67, 127.55,120.92, 117.28, 116.31, 114.82, 114.68, 82.38, 75.70, 70.67, 48.55,35.96, 15.11; ESIMS m/z 413 (([M+Na]⁺)).

Example 4C: Preparation of1-((1R,2S)-2-(benzyloxy)-1-cyclopentylpropoxy)-3-chlorobenzene

To a suspension of potassium tert-butoxide (KOt-Bu; 314 mg, 2.80 mmol)in anhydrous N,N-dimethylformamide (DMF; 2 mL) was added(1R,2S)-2-(benzyloxy)-1-cyclopentylpropan-1-ol (469 mg, 2.00 mmol) atroom temperature, and the resulting orange solution was stirred for 5min, treated with 1-chloro-3-fluorobenzene (643 μL, 6.00 mmol), andheated to and stirred at 60° C. overnight. The cooled reaction mixturewas quenched with glacial acetic acid (HOAc; 300 μL), diluted withhexanes (2 mL), and the resulting suspension was purified by flashcolumn chromatography (SiO₂, 2→8% acetone in hexanes) to afford thetitle compound (637 mg, 92%) as a colorless oil: IR (Thin film) 3065,2949, 2866, 1590, 1474, 1452 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.35-7.30(m, 2H), 7.29-7.26 (m, 3H), 7.14 (t, J=8.1 Hz, 1H), 7.05 (t, J=2.2 Hz,1H), 6.88 (dd, J=8.2, 2.1 Hz, 2H), 4.61 (d, J=11.7 Hz, 1H), 4.49 (d,J=11.8 Hz, 1H), 4.23 (dd, J=7.4, 3.7 Hz, 1H), 3.70 (qd, J=6.3, 3.7 Hz,1H), 2.30-2.12 (m, 1H), 1.85-1.74 (m, 1H), 1.71-1.64 (m, 1H), 1.66-1.46(m, 4H), 1.45-1.35 (m, 1H), 1.25 (d, J=6.3 Hz, 3H), 1.23-1.15 (m, 1H);¹³C NMR (126 MHz, CDCl₃) δ 160.99, 138.48, 134.62, 130.03, 128.33,127.51, 127.48, 120.72, 116.88, 114.73, 85.07, 76.56, 70.85, 42.16,29.40, 28.98, 25.46, 25.12, 14.78.

Example 4D: Preparation of4-((1R,2S)-2-(benzyloxy)-1-(cyclopropylmethoxy)-propyl)-1,1′-biphenyl

To a solution of(1R,2S)-1-([1,1′-biphenyl]-4-yl)-2-(benzyloxy)propan-1-ol (272 mg, 0.854mmol) in anhydrous DMF (2.8 mL) at 0° C. was added sodium hydride (NaH;59.8 mg, 1.50 mmol, 60 wt % in mineral oil) and the reaction mixture wasstirred at 0° C. for 15 min. The mixture was removed from the ice bath,stirred for an additional 15 min, cooled back to 0° C., and treated with(bromomethyl)cyclopropane (84 μL, 0.854 mmol). After 10 min, thereaction vessel was removed from the ice bath and the mixture was warmedto and stirred at room temperature overnight. The reaction mixture wascarefully quenched by the addition of H₂O followed by stirring for 10min and the phases were separated. The aq. phase was extracted with Et₂O(3×), and the combined organic phases were dried over Na₂SO₄, filtered,and concentrated. The resulting oil was purified by flash columnchromatography (SiO₂, 0→10% acetone in hexanes) to afford the titlecompound (251 mg, 79%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ7.64-7.60 (m, 2H), 7.57 (d, J=8.2 Hz, 2H), 7.48-7.32 (m, 5H), 7.24-7.19(m, 3H), 7.10-7.06 (m, 2H), 4.46 (d, J=11.9 Hz, 1H), 4.30 (d, J=11.9 Hz,1H), 4.27 (d, J=6.4 Hz, 1H), 3.64 (p, J=6.2 Hz, 1H), 3.28-3.20 (m, 2H),1.32 (d, J=6.2 Hz, 3H), 1.12-1.01 (m, 1H), 0.56-0.45 (m, 2H), 0.22-0.10(m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 141.03, 140.33, 139.54, 138.60,128.75, 128.18, 128.14, 127.67, 127.30, 127.18, 127.06, 126.73, 84.36,78.56, 73.75, 71.47, 16.71, 10.74, 3.18, 2.83; ESIMS m/z 395(([M+Na]⁺)).

Example 4E: Preparation of(S)-(((1-(tert-butoxy)propan-2-yl)oxy)methyl)benzene

To a solution of (S)-2-(benzyloxy)propan-1-ol (300 mg, 1.80 mmol) inanhydrous CH₂Cl₂ (9.0 mL) were added di-tert-butyl dicarbonate (Boc₂O;985 mg, 4.51 mmol) and scandium trifluoromethanesulfonate (Sc(OTf)₃; 89mg, 0.180 mmol) at room temperature, and the resulting solution wasstirred at room temperature for 20 h. The mixture was treated withadditional Boc₂O (400 mg) and the mixture was heated to and stirred at40° C. for 4 h. The reaction mixture was cooled to room temperature,concentrated, and the residue purified by flash column chromatography(SiO₂, 2→12% acetone in hexanes) to provide the title compound (223 mg,56%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.29 (m, 4H),7.29-7.23 (m, 1H), 4.63 (s, 2H), 3.64 (h, J=6.2 Hz, 1H), 3.48 (dd,J=9.2, 5.7 Hz, 1H), 3.27 (dd, J=9.2, 5.6 Hz, 1H), 1.23-1.16 (m, 12H);¹³C NMR (126 MHz, CDCl₃) δ 139.13, 128.26, 127.61, 127.33, 74.56, 72.84,71.21, 66.08, 27.52, 17.70; ESIMS m/z 245 (([M+Na]⁺)).

Example 4F: Preparation of((((1R,2S)-1-cyclopentyl-1-((2-methylallyl)oxy)propan-2-yl)oxy)methyl)benzene

To a suspension of KOt-Bu (314 mg, 2.80 mmol) in anhydrous DMF (2 mL)was added (1R,2S)-2-(benzyloxy)-1-cyclopentylpropan-1-ol (469 mg, 2.00mmol). The resulting orange solution was stirred at room temperature for5 min, treated with 3-bromo-2-methylprop-1-ene (605 μL, 6.00 mmol), andwarmed to and stirred at 60° C. overnight. The cooled reaction mixturewas quenched with glacial HOAc (300 μL), diluted with hexanes (2 mL),and the resulting suspension purified by flash column chromatography(SiO₂, 2→8% acetone in hexanes) to afford the title compound (476 mg,83%) as a colorless oil: IR (Thin film) 3066, 2947, 2865, 1726, 1656,1452 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.34 (d, J=4.3 Hz, 4H), 7.31-7.23(m, 1H), 4.98 (dt, J=2.3, 1.2 Hz, 1H), 4.85-4.78 (m, 1H), 4.58 (d,J=11.9 Hz, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.23 (d, J=12.0 Hz, 1H), 3.96(d, J=12.0 Hz, 1H), 3.58 (qd, J=6.4, 2.7 Hz, 1H), 3.32 (dd, J=8.1, 2.6Hz, 1H), 2.01-1.88 (m, 1H), 1.88-1.79 (m, 1H), 1.76 (d, J=1.3 Hz, 3H),1.66-1.57 (m, 3H), 1.54-1.45 (m, 2H), 1.44-1.35 (m, 1H), 1.22 (d, J=6.3Hz, 3H), 1.20-1.12 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 143.21, 139.04,128.29, 127.38, 127.33, 111.68, 85.41, 77.83, 76.21, 70.61, 42.49,29.89, 29.64, 25.44, 25.21, 19.90, 14.25.

Example 4G: Preparation of((1R,2S)-2-(benzyloxy)-1-methoxypropyl)adamantane

To a solution of (1R,2S)-1-(adamantan-1-yl)-2-(benzyloxy)propan-1-ol(0.550 g, 1.831 mmol) in CH₂Cl₂ (7.32 ml) at 0° C. was added ProtonSponge® (0.785 g, 3.66 mmol) and trimethyloxonium tetrafluoroborate(0.406 g, 2.75 mmol), and the reaction mixture was warmed to roomtemperature and stirred for 6 h. An additional equivalent of both ProtonSponge® and trimethyloxonium tetrafluoroborate were added, and themixture was stirred at room temperature overnight. The reaction mixturewas quenched with sat. NaHCO₃, the phases were separated, and theproducts were extracted from the aqueous phase with CH₂Cl₂ (2×). Thecombined organic phases were washed with 1N NaHSO₄ (2×), dried overNa₂SO₄, filtered and concentrated. The crude material was purified byflash column chromatography (SiO₂, 0→20% acetone in hexanes) to affordthe title compound (501 mg, 87%) as a colorless oil: IR (Thin film)2899.51, 1451.42, 1105.09, 1091.88 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.39-7.31 (m, 5H), 4.53 (d, J=11.9 Hz, 1H), 4.47 (d, J=11.9 Hz, 1H),3.73 (qd, J=6.2, 2.2 Hz, 1H), 3.50 (s, 3H), 2.84 (d, J=2.3 Hz, 1H),2.03-1.85 (d, J=3.4 Hz, 3H), 1.81-1.47 (m, 12H), 1.24 (d, J=6.3 Hz, 3H);¹³C NMR (101 MHz, CDCl₃) δ 138.99, 128.30, 127.48, 127.35, 91.85, 75.25,70.22, 61.34, 38.89, 37.27, 37.18, 28.40, 15.91; HRMS-ESI m/z(([M+Na]⁺)) calcd for C₂₁H₃₀NaO₂, 337.2138; found, 337.2143.

Example 4H: Preparation of((((2S)-1-(cyclopent-2-en-1-yloxy)propan-2-yl)oxy)-methyl)benzene

To a solution of (S)-2-(benzyloxy)propan-1-ol (300 mg, 1.81 mmol), DPPF(100 mg, 0.180 mmol), and Pd₂(dba)₃ (83 mg, 0.090 mmol) in anhydrous THF(9 mL) at 65° C. was added tert-butyl cyclopent-2-en-1-yl carbonate (665mg, 3.61 mmol), and the reaction mixture was stirred at 65° C. for 7 h,cooled to room temperature, concentrated, and purified by flash columnchromatography (SiO₂, 1→16% acetone in hexanes) to provide the titlecompound (192 mg, 0.826 mmol, 45.7%) as a light yellow oil. ¹H NMR and¹³C NMR show the product to be a 1:1 mixture of diastereomers, asreflected in the extra carbons present in the ¹³C spectrum: ¹H NMR (400MHz, CDCl₃) δ 7.42-7.30 (m, 4H), 7.30-7.19 (m, 1H), 6.01 (dtd, J=5.6,2.2, 1.1 Hz, 1H), 5.91-5.81 (m, 1H), 4.70-4.53 (m, 3H), 3.78-3.64 (m,1H), 3.54 (ddd, J=11.3, 9.9, 5.8 Hz, 1H), 3.41 (ddd, J=9.8, 7.4, 5.1 Hz,1H), 2.56-2.42 (m, 1H), 2.32-2.20 (m, 1H), 2.20-2.07 (m, 1H), 1.86-1.72(m, 1H), 1.20 (d, J=6.3 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 139.02,135.64, 135.60, 130.86, 130.78, 128.28, 127.61, 127.60, 127.37, 85.27,74.24, 74.22, 72.52, 72.46, 71.17, 31.10, 31.09, 29.66, 29.60, 17.56,17.54; ESIMS m/z 255.3 (([M+Na]⁺)).

Example 5: Preparation of3-(((2S,3R)-2-(benzyloxy)-4-ethylhexan-3-yl)oxy)-1,1′-biphenyl

A mixture of1-(((2S,3R)-2-(benzyloxy)-4-ethylhexan-3-yl)oxy)-3-bromobenzene (555 mg,1.418 mmol), sodium carbonate (Na₂CO₃; 451 mg, 4.25 mmol), andphenylboronic acid (501 mg, 4.11 mmol) in dioxane (5.3 mL) and H₂O (1.8mL) was deoxygenated by evacuating under gentle vacuum and back-fillingwith N₂ (3×), and the degassed mixture was treated withtetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄; 164 mg, 0.142mmol). The degassing procedure was repeated and the mixture was heatedto and stirred at 80° C. for 4 h, cooled to room temperature, anddiluted with H₂O (20 mL). The phases were separated and the aq. phasewas extracted with CH₂Cl₂ (20 mL). The organic phase was dried bypassing through a phase separator cartridge and then evaporated. Theresulting oil was purified by flash column chromatography (SiO₂, 1→5%EtOAc in hexanes) to afford the title compound (540 mg, 98%) as acolorless oil: IR (Thin film) 2961, 2931, 2873, 1595, 1569, 1476 cm⁻¹;¹H NMR (500 MHz, CDCl₃) δ 7.58-7.51 (m, 2H), 7.42-7.37 (m, 2H),7.36-7.27 (m, 7H), 7.23 (dd, J=2.5, 1.7 Hz, 1H), 7.14 (ddd, J=7.6, 1.7,1.0 Hz, 1H), 6.97 (ddd, J=8.2, 2.6, 0.9 Hz, 1H), 4.63 (d, J=11.6 Hz,1H), 4.48 (d, J=11.7 Hz, 1H), 4.42 (t, J=5.1 Hz, 1H), 3.82 (qd, J=6.2,5.2 Hz, 1H), 1.75-1.56 (m, 2H), 1.46-1.35 (m, 3H), 1.30 (d, J=6.2 Hz,3H), 0.91 (t, J=7.4 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H); ¹³C NMR (126 MHz,CDCl₃) δ 160.44, 142.57, 141.18, 138.56, 129.60, 128.66, 128.30, 127.62,127.46, 127.24, 127.13, 119.38, 114.98, 114.77, 81.99, 75.43, 70.76,43.00, 22.36, 21.44, 15.70, 11.85, 11.44.

Example 6A, Step 1: Preparation of(3S,4R,5S)-5-(benzyloxy)-3-(4-fluorobenzyl)-4-phenoxyhexan-1-ol

To a solution of 9-borabicyclo[3.3.1]nonane (9-BBN; 17.90 mL, 8.95 mmol,0.5 M in THF) was added1-((2S,3R,4S)-4-(benzyloxy)-3-phenoxy-2-vinylpentyl)-4-fluorobenzene(2.33 g, 5.97 mmol) and the reaction mixture was stirred at roomtemperature for 2 h, cooled to 0° C., and treated dropwise with aq. 2 NNaOH (11.9 mL, 23.9 mmol) followed by aq. 30% H₂O₂ (2.44 mL, 23.9 mmol).The mixture was removed from the cold bath and stirred for 45 min,cooled back to 0° C., and quenched by the addition of sat. aq. sodiumbisulfite (NaHSO₃). The phases were separated and the aq. phase wasextracted with EtOAc (3×20 mL). The combined organic phases were driedover MgSO₄, filtered, and evaporated to give an oil which was purifiedby flash column chromatography (SiO₂, 4→20% acetone in hexanes) toafford the title compound (2.32 g, 95%) as a clear, colorless oil: ¹HNMR (400 MHz, CDCl₃) δ 7.36 (d, J=4.5 Hz, 4H), 7.34-7.27 (m, 1H),7.27-7.18 (m, 2H), 7.11-7.03 (m, 2H), 6.97-6.87 (m, 3H), 6.85-6.76 (m,2H), 4.67 (d, J=11.4 Hz, 1H), 4.41 (d, J=11.4 Hz, 1H), 4.31 (dd, J=7.5,2.4 Hz, 1H), 3.97-3.80 (m, 1H), 3.56 (p, J=6.0 Hz, 2H), 3.00 (dd,J=13.8, 6.2 Hz, 1H), 2.55 (dd, J=13.8, 8.7 Hz, 1H), 2.29 (pd, J=8.3, 2.4Hz, 1H), 1.76-1.61 (m, 1H), 1.58-1.48 (m, 2H), 1.28 (d, J=6.1 Hz, 3H);¹³C NMR (101 MHz, CDCl₃) δ 162.54, 160.11, 158.77, 138.25, 136.81,136.78, 130.72, 130.64, 129.60, 128.47, 127.96, 127.76, 120.95, 115.63,115.13, 114.92, 81.00, 75.19, 70.83, 61.34, 39.38, 35.90, 33.50, 16.82;ESIMS m/z 431 (([M+Na]⁺)).

Example 6A, Step 2a: Preparation of1-((2S,3R,4S)-4-(benzyloxy)-2-(2-methoxyethyl)-3-phenoxypentyl)-4-fluorobenzene

To a solution of(3S,4R,5S)-5-(benzyloxy)-3-(4-fluorobenzyl)-4-phenoxyhexan-1-ol (390 mg,0.955 mmol) in anhydrous CH₂Cl₂ (10 mL) at 0° C. were addedN¹,N¹,N⁸,N⁸-tetramethylnaphthalene-1,8-diamine (614 mg, 2.86 mmol)followed by trimethyloxonium tetrafluoroborate (282 mg, 1.91 mmol), andthe mixture was stirred at 0° C. for 4 h and quenched with by theaddition of aq. 1 N HCl (10 mL). The phases were separated and the aq.phase was extracted with CH₂Cl₂ (2×10 mL). The organic phases werecombined, dried over Na₂SO₄, filtered, and evaporated to an oily whitesolid which was suspended in hexanes, filtered through Celite®, andconcentrated to give an oil. The residual oil was purified by flashcolumn chromatography (SiO₂, 1→20% acetone in hexanes) to afford thetitle compound (239 mg, 59%) as a clear, colorless oil: ¹H NMR (400 MHz,CDCl₃) δ 7.35 (d, J=4.1 Hz, 4H), 7.30 (dt, J=9.1, 4.5 Hz, 1H), 7.22 (t,J=8.0 Hz, 2H), 7.08 (dd, J=8.2, 5.7 Hz, 2H), 6.98-6.87 (m, 3H), 6.83 (d,J=8.4 Hz, 2H), 4.65 (d, J=11.5 Hz, 1H), 4.41 (d, J=11.5 Hz, 1H), 4.32(dd, J=7.0, 2.5 Hz, 1H), 3.85 (p, J=6.2 Hz, 1H), 3.29 (t, J=6.8 Hz, 2H),3.19 (d, J=1.3 Hz, 3H), 3.01 (dd, J=13.8, 5.9 Hz, 1H), 2.56 (dd, J=13.9,8.8 Hz, 1H), 2.37-2.22 (m, 1H), 1.78-1.64 (m, 1H), 1.59-1.47 (m, 1H),1.27 (d, J=6.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 161.27 (d, J=243.4Hz), 159.11, 138.44, 136.89 (d, J=3.2 Hz), 130.65 (d, J=7.7 Hz), 129.46,128.38, 127.76, 127.59, 120.70, 115.73, 114.93 (d, J=21.0 Hz), 81.11,75.18, 71.07, 70.74, 58.39, 39.20, 35.38, 30.20, 16.67; ESIMS m/z 423(([M+H]⁺)).

Example 6A, Step 2b: Preparation of1-((2S,3R,4S)-4-(benzyloxy)-2-(2-(tert-butoxy)ethyl)-3-phenoxypentyl)-4-methoxybenzene

To a solution of (3S,4R,5S)-5-(benzyloxy)-3-(4-methoxybenzyl)-4-phenoxyhexan-1-ol (1.99 g, 4.73mmol) and (R)-2-benzyl 1-tert-butyl aziridine-1,2-dicarboxylate (1.44 g,5.21 mmol) in anhydrous CH₂Cl₂ (20 mL) at 0° C. was added Sc(OTf)₃(0.233 g, 0.473 mmol), and the reaction mixture was stirred at 0° C. for40 min and then allowed to warm room temperature overnight as the icemelted. The mixture was quenched with sat. aq. NaHCO₃ (25 mL),partitioned between H₂O (25 mL) and CH₂Cl₂ (50 mL), and the phases wereseparated. The aq. phase was extracted with CH₂Cl₂ (2×25 mL) and thecombined organic phases were dried over Na₂SO₄, filtered, and evaporatedto a colorless oil, which was purified by flash column chromatography(SiO₂, 2→25% acetone in hexanes) to afford the title compound (320 mg,14%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J=4.4 Hz,4H), 7.33-7.26 (m, 1H), 7.21 (t, J=8.0 Hz, 2H), 7.07 (d, J=8.6 Hz, 2H),6.88 (t, J=8.6 Hz, 3H), 6.79 (d, J=8.6 Hz, 2H), 4.63 (d, J=11.5 Hz, 1H),4.45-4.36 (m, 2H), 3.86 (p, J=6.2 Hz, 1H), 3.78 (s, 3H), 3.32-3.18 (m,2H), 2.99 (dd, J=13.9, 5.8 Hz, 1H), 2.54 (dd, J=13.9, 8.8 Hz, 1H),2.37-2.22 (m, 1H), 1.66 (dq, J=14.0, 7.0 Hz, 1H), 1.60-1.46 (m, 1H),1.27 (d, J=6.1 Hz, 3H), 1.08 (s, 9H); ¹³C NMR (151 MHz, CDCl₃) δ 159.44,157.75, 138.64, 133.45, 130.26, 129.37, 128.32, 127.68, 127.47, 120.52,115.94, 113.63, 81.62, 75.33, 72.50, 70.73, 60.26, 55.29, 39.62, 35.32,31.25, 27.51, 16.62; ESIMS m/z 499 (([M+Na]⁺)).

Example 6B, Step 1: Preparation of(2S,3S,4S)-4-(benzyloxy)-3-phenoxy-2-propoxypentan-1-ol

A solution of(((2S,3S,4S)-2-(benzyloxy)-4-propoxyhex-5-en-3-yl)oxy)benzene (500 mg,1.47 mmol) and NaHCO₃ (12.3 mg, 0.147 mmol) in anhydrous MeOH (0.44 mL)and CH₂Cl₂ (14 mL) was treated with ozone (O₃) at −78° C. until thesolution turned from colorless to blue. The reaction mixture was purgedwith oxygen (O₂) until colorless, treated with additional MeOH (4 mL)followed by NaBH₄ (167 mg, 4.41 mmol), and then warmed to roomtemperature and stirred for 4 h. The mixture was quenched with H₂O,diluted with CH₂Cl₂, and the phases were separated. The aq. phase wasextracted with CH₂Cl₂ (2×) and the combined organic phases were washedwith brine, dried over MgSO₄, filtered, and evaporated. The resultingcrude residue was purified by flash column chromatography (SiO₂, 0→100%EtOAc in hexanes) to afford the title compound (458 mg, 91%) as acolorless oil: IR (Thin film) 3453, 2934, 2875, 1597, 1493, 1237 cm⁻¹;¹H NMR (400 MHz, CDCl₃) δ 7.36-7.22 (m, 7H), 7.06-7.02 (m, 2H),6.97-6.91 (m, 1H), 4.63 (d, J=11.5 Hz, 1H), 4.51-4.44 (m, 2H), 3.95-3.87(m, 1H), 3.79-3.66 (m, 3H), 3.60-3.49 (m, 2H), 2.08-2.04 (m, 1H),1.60-1.51 (m, 2H), 1.29 (d, J=6.3 Hz, 3H), 0.86 (t, J=7.4 Hz, 3H); ESIMSm/z 345 (([M+H]⁺)).

Example 6B, Step 2: Preparation of(((2S,3S,4S)-4-(benzyloxy)-1-methoxy-2-propoxypentan-3-yl)oxy)benzene

A solution of (2S,3S,4S)-4-(benzyloxy)-3-phenoxy-2-propoxypentan-1-ol(452 mg, 1.31 mmol), Proton Sponge® (1687 mg, 7.87 mmol), andtrimethyloxonium tetrafluoroborate (485 mg, 3.28 mmol) in anhydrousCH₂Cl₂ (10 mL) was stirred at room temperature for 8 h, and the reactionmixture was quenched by the addition of sat. aq. NaHCO₃, diluted withCH₂Cl₂, and the phases were separated. The aq. phase was extracted withCH₂Cl₂ and the combined organic phases were washed with 1 M aq. HCl(3×), washed with brine, dried over MgSO₄, filtered, and evaporated. Theresidue was purified by flash column chromatography (SiO₂, 0→100% EtOAcin hexanes) to afford the title compound (370 mg, 79%) as a colorlessoil: IR (Thin film) 2930, 2875, 1597, 1493, 1237 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 7.35-7.21 (m, 7H), 7.08-7.03 (m, 2H), 6.95-6.89 (m, 1H), 4.64(d, J=11.5 Hz, 1H), 4.50-4.44 (m, 2H), 4.02-3.93 (m, 1H), 3.89-3.83 (m,1H), 3.64-3.56 (m, 1H), 3.54-3.48 (m, 1H), 3.47-3.39 (m, 2H), 3.24 (s,3H), 1.63-1.53 (m, 2H), 1.26 (d, J=6.3 Hz, 3H), 0.87 (t, J=7.4 Hz, 3H);ESIMS m/z 359 (([M+H]⁺)).

Example 6C: Preparation of(((1S,2S,3S)-3-(benzyloxy)-1-cyclopropyl-1-propoxybutan-2-yl)oxy)benzene

To a solution of(((2S,3S,4S)-2-(benzyloxy)-4-propoxyhex-5-en-3-yl)oxy)benzene (500 mg,1.47 mmol) and diethylzinc (Et₂Zn; 1 M in hexanes, 14.7 mL, 14.7 mmol)in Et₂O (10 mL) was added diiodomethane (CH₂12; 2.37 mL, 29.4 mmol) at0° C. dropwise, and the reaction mixture was warmed to room temperatureover a 15 min period and stirred for 2 d. Excess Et₂Zn (5.0 mL, 5.0mmol) and CH₂I₂ (0.83 mL, 10.3 mmol) were added at 0° C. and thereaction was warmed to and stirred at 45° C. 20 h. The reaction mixturewas quenched by the addition of sat. aq. NH₄Cl and extracted with Et₂O.The combined organic extracts were washed with brine, dried over MgSO₄,filtered, concentrated, and purified by column chromatography (SiO₂,hexanes/EtOAc gradient) to furnish the title compound (113 mg, 22%) as acolorless oil: IR (neat) 2932, 2874, 1597, 1493, 1239, 1084 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 7.39-7.20 (m, 7H), 7.09-7.04 (m, 2H), 6.94-6.88 (m,1H), 4.62 (d, J=11.4 Hz, 1H), 4.47 (d, J=11.4 Hz, 1H), 4.35 (dd, J=7.3,2.9 Hz, 1H), 4.08-4.00 (m, 1H), 3.82-3.74 (m, 1H), 3.35-3.28 (m, 1H),2.98 (dd, J=9.0, 2.9 Hz, 1H), 1.66-1.55 (m, 2H), 1.26 (d, J=6.2 Hz, 3H),0.98-0.85 (m, 4H), 0.70-0.62 (m, 1H), 0.49-0.41 (m, 1H), 0.38-0.30 (m,1H), 0.21-0.13 (m, 1H); HRMS-ESI (m/z) [M]⁺ calcd for C₂₃H₃₀O₃,354.2195; found, 354.2195.

Example 7, Step 1: Preparation of(2R,3S)-3-(benzyloxy)-2-phenoxybutan-1-ol

To a solution of (((2S,3R,E)-2-(benzyloxy)hex-4-en-3-yl)oxy)benzene (740mg, 2.62 mmol) in a mixture of CH₂Cl₂ (11 mL) and MeOH (1.2 mL) wereadded 2 drops of a 1% solution of Sudan III in CH₂Cl₂. The resultingpink solution was cooled to −78° C. and O₃ was bubbled through thereaction mixture until the pink color faded. The solution was purgedwith O₂ for 5 min, placed under an N₂ atmosphere, and treated with NaBH₄(297 mg, 7.86 mmol). The reaction mixture was slowly warmed to roomtemperature, stirred overnight, diluted with CH₂Cl₂ (10 mL), andquenched with sat. aq. NH₄Cl (10 mL). The phases were separated, the aq.phase was extracted with CH₂Cl₂ (2×10 mL), and the combined organicphases were dried by passing through a phase separator cartridge andevaporated. The resulting crude material was purified by flash columnchromatography (SiO₂, 0→60% EtOAc in hexanes) to afford the titlecompound (610 mg, 85%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ7.37-7.25 (m, 7H), 7.01-6.92 (m, 3H), 4.67 (d, J=11.6 Hz, 1H), 4.55 (d,J=11.5 Hz, 1H), 4.23 (app dt, J=6.0, 4.5 Hz, 1H), 3.97-3.84 (m, 3H),2.30 (app t, J=6.4 Hz, 1H), 1.31 (d, J=6.3 Hz, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 158.01, 138.07, 129.66, 128.49, 127.82, 127.81, 121.49, 116.16,81.18, 75.24, 71.51, 62.02, 16.82; ESIMS m/z 273 (([M+H]⁺)).

Example 7, Step 2a: Preparation of(((2R,3S)-3-(benzyloxy)-1-propoxybutan-2-yl)oxy)benzene

To a solution of (2R,3S)-3-(benzyloxy)-2-phenoxybutan-1-ol (150 mg,0.551 mmol) in DMF (2.7 mL) at 0° C. was added NaH (44.1 mg, 1.10 mmol,60 wt % in mineral oil), and the reaction mixture was stirred at 0° C.for 10 min, removed from the cold bath and stirred at room temperaturefor 15 min. treated with propyl 4-methylbenzenesulfonate (237 μL, 1.24mmol), and stirred at room temperature for 16 h. The mixture wasquenched by the addition of sat. aq. NH₄Cl (7 mL), diluted with Et₂O (10mL), and the phases were separated. The aq. phase was extracted withEt₂O (2×10 mL) and the combined organic phases were washed with brine (5mL), dried over Na₂SO₄, filtered and evaporated. The crude residue waspurified by flash column chromatography (SiO₂, 0→30% EtOAc in hexanes)to afford the title compound (125 mg, 72%) as a colorless oil: ¹H NMR(400 MHz, CDCl₃) δ 7.35-7.22 (m, 7H), 7.03-6.90 (m, 3H), 4.67-4.54 (m,2H), 4.36 (app td, J=5.1, 3.9 Hz, 1H), 3.89 (qd, J=6.4, 5.0 Hz, 1H),3.80-3.67 (m, 2H), 3.41 (app td, J=6.7, 2.6 Hz, 2H), 1.64-1.50 (m, 2H),1.29 (d, J=6.4 Hz, 3H), 0.89 (app t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 158.67, 138.64, 129.41, 128.32, 127.69, 127.51, 121.09, 116.52,80.85, 74.38, 73.30, 71.46, 69.48, 22.87, 16.26, 10.58; ESIMS m/z 315(([M+H]⁺)).

Example 7, Step 2b: Preparation of(((2R,3S)-3-(benzyloxy)-1-phenoxybutan-2-yl)oxy)benzene

To a solution of (2R,3S)-3-(benzyloxy)-2-phenoxybutan-1-ol (290 mg, 1.06mmol) in CH₂Cl₂ (5.3 mL) were added diacetoxycopper (19.3 mg, 0.106mmol) and Ph₃Bi(OAc)₂ (654 mg, 1.17 mmol), and the mixture was stirredovernight at room temperature, filtered through a pad of Celite® rinsingwith CH₂Cl₂ (2×10 mL), and concentrated. The crude residue was purifiedby flash column chromatography (SiO₂, 0→35% EtOAc in hexanes) to affordthe title compound (290 mg, 76%) as a colorless oil: ¹H NMR (400 MHz,CDCl₃) δ 7.31-7.24 (m, 9H), 7.04-6.83 (m, 6H), 4.66 (d, J=11.7 Hz, 1H),4.61-4.50 (m, 2H), 4.34-4.21 (m, 2H), 4.01 (qd, J=6.3, 5.3 Hz, 1H), 1.36(d, J=6.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 158.72, 158.40, 138.34,129.53, 129.43, 128.37, 127.80, 127.62, 121.44, 120.93, 116.56, 114.70,80.25, 74.09, 71.58, 66.73, 16.46; ESIMS m/z 371 (([M+Na]⁺)).

Example 8A: Preparation of(1R,2S)-1-(3-chlorophenoxy)-1-cyclopentylpropan-2-ol

To a solution of1-((1R,2S)-2-(benzyloxy)-1-cyclopentylpropoxy)-3-chlorobenzene (630 mg,1.83 mmol) in a mixture of ethanol (EtOH; 6.1 mL) and cyclohexene (3.0mL) was added 10% palladium on carbon (Pd/C; 97 mg, 0.091 mmol) and theresulting suspension was heated to and stirred at 65° C. for 2 h. Thereaction mixture was filtered through a plug of Celite® and the filtratewas evaporated to give the title compound (476 mg, 97%) as a colorlessoil: IR (Thin film) 3351, 2951, 2867, 1590, 1473, 1427, 1228 cm⁻¹; ¹HNMR (500 MHz, CDCl₃) δ 7.17 (t, J=8.1 Hz, 1H), 7.03 (t, J=2.3 Hz, 1H),6.94-6.87 (m, 2H), 4.21 (dd, J=8.0, 3.4 Hz, 1H), 3.99 (qd, J=6.4, 3.3Hz, 1H), 2.21-2.07 (m, 1H), 1.87-1.77 (m, 1H), 1.70 (dtd, J=11.7, 7.6,3.8 Hz, 1H), 1.66-1.44 (m, 5H), 1.38-1.30 (m, 1H), 1.27 (d, J=6.4 Hz,3H), 1.31-1.19 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 160.86, 134.83,130.23, 121.13, 116.87, 114.59, 86.65, 69.41, 42.15, 29.68, 29.22,25.23, 25.03, 17.85.

Example 8B: Preparation of (2S,3R,4R)-4-benzyl-3-isobutoxyhexan-2-ol

A Parr bottle was charged with a suspension of((((2S,3R,4S)-4-benzyl-3-((2-methylallyl)oxy)hex-5-en-2-yl)oxy)methyl)benzene(1.85 g, 5.28 mmol) and 10% Pd/C (0.056 g, 0.53 mmol) in EtOH (10 mL)and the bottle was evacuated under gentle vacuum and back-filled withhydrogen gas (H₂; 3×). The bottle was loaded into the Paar shaker andthe system was pressurized to 50 pounds per square inch (psi) with H₂and agitated overnight at room temperature. The reaction mixture wasfiltered through Celite® and the filtrate was evaporated to afford thetitle compound (1.36 g, 97%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃)δ 7.30-7.24 (m, 2H), 7.22-7.14 (m, 3H), 3.96 (h, J=6.3 Hz, 1H), 3.39(dd, J=8.6, 6.3 Hz, 1H), 3.30 (dd, J=8.6, 6.6 Hz, 1H), 3.21-3.17 (m,1H), 3.05 (dd, J=13.8, 4.6 Hz, 1H), 2.44 (dd, J=13.8, 9.8 Hz, 1H), 1.86(m, 2H), 1.76 (d, J=5.6 Hz, 1H), 1.45-1.24 (m, 2H), 1.25 (d, J=6.3 Hz,3H), 0.95 (dd, J=6.7, 4.3 Hz, 6H), 0.85 (t, J=7.5 Hz, 3H); ¹³C NMR (100MHz, CDCl₃) δ 142.04, 129.13, 128.19, 125.59, 83.76, 79.27, 68.23,42.93, 35.69, 29.24, 22.76, 19.54, 19.50, 19.02, 11.30; [α]=3.048 (2.1g/100 mL, CHCl₃).

Example 8C: Preparation of(2S,3R)-4-(cyclopentylmethyl)-3-(cyclopropylmethoxy)hexan-2-ol

To a solution of1-((2S,3R,4S)-4-(benzyloxy)-2-(2-methoxyethyl)-3-phenoxypentyl)-4-fluorobenzene(215 mg, 0.509 mmol) in EtOAc (5 mL) was added 5% Pd/C (54.2 mg, 0.025mmol), and the reaction vessel was evacuated under gentle vacuum andback-filled with H₂ (3×). The mixture was placed under approximately 1Atm of H₂ (balloon) and stirred overnight at room temperature. Thereaction mixture was filtered through a plug of Celite® and concentratedto provide the title compound (176 mg, 99%) as a clear, colorless oil:¹H NMR (400 MHz, CDCl₃) δ 7.30-7.21 (m, 2H), 7.21-7.14 (m, 2H),7.02-6.85 (m, 5H), 4.26 (dd, J=6.2, 3.9 Hz, 1H), 4.11 (h, J=6.2 Hz, 1H),3.40-3.24 (m, 2H), 3.21 (s, 3H), 3.11 (dd, J=13.9, 5.5 Hz, 1H), 2.55(dd, J=14.0, 9.0 Hz, 1H), 2.37-2.23 (m, 1H), 1.80-1.66 (m, 2H),1.66-1.54 (m, 1H), 1.29 (d, J=6.3 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ161.31 (d, J=243.7 Hz), 159.11, 136.75 (d, J=3.2 Hz), 130.55 (d, J=7.7Hz), 129.57, 120.97, 115.83, 115.07 (d, J=21.0 Hz), 82.44, 70.82, 68.31,58.46, 39.14, 35.48, 30.06, 20.18; ESIMS m/z 333 (([M+H]⁺)).

Example 8D: Preparation of(1S,2S)-1-phenoxy-1-(thiophen-2-yl)propan-2-ol

To a solution of2-((1S,2S)-2-((4-methoxybenzyl)oxy)-1-phenoxypropyl)thiophene (0.223 g,0.630 mmol) in a mixture of CH₂Cl₂ (3 mL) and H₂O (0.3 mL) at 0° C. wasadded 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile(0.150 g, 0.661 mmol), and the reaction mixture was stirred for 30 minquenched by the addition of aq. 1 N NaOH (0.66 mL), and diluted withCH₂Cl₂ (10 mL). The phases were separated and the aq. phase wasextracted with CH₂Cl₂ (2×10 mL). The combined organic phases were driedover Na₂SO₄, filtered, evaporated, and purified by flash columnchromatography (SiO₂, 2→20% acetone in hexanes) to afford the titlecompound (116 mg, 75%) as a colorless oil: IR (Thin film) 3390, 2923,2851, 2865, 1597 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.33-7.16 (m, 3H), 7.07(ddd, J=3.5, 1.2, 0.7 Hz, 1H), 7.03-6.88 (m, 4H), 5.26 (d, J=4.9 Hz,1H), 4.28-4.09 (m, 1H), 2.08 (d, J=4.9 Hz, 1H), 1.29 (d, J=6.3 Hz, 3H);¹³C NMR (101 MHz, CDCl₃) δ 157.60, 140.58, 129.43, 126.59, 126.50,125.94, 121.60, 116.21, 80.60, 70.73, 18.33.

Example 8E: Preparation of (2S,3R)-3-(benzyloxy)hex-5-en-2-ol

To a solution of(((2S,3R)-3-(benzyloxy)hex-5-en-2-yl)oxy)triisopropylsilane (4.04 g,11.1 mmol) in THF (56 mL) at 0° C. was added tetra-N-butyl ammoniumfluoride (TBAF; 14.7 mL, 14.7 mmol, 1 M in THF) over a 5 min period, andthe reaction mixture was warmed to room temperature and stirred for 4 h,poured into sat. aq. NH₄Cl (100 mL), and diluted with EtOAc (100 mL).The phases were separated and the aq. phase was extracted with EtOAc(2×100 mL). The combined organic phases were dried over MgSO₄, filtered,and concentrated to a yellow oil, which was purified by flash columnchromatography (SiO₂, 0→25% EtOAc in hexanes) to afford the titlecompound (1.91 g, 83%) as a clear, colorless oil: IR (neat) 3419, 2977,2872, 1454, 1069, 696 cm¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.20 (m, 5H),5.87 (ddt, J=17.2, 10.2, 7.1 Hz, 1H), 5.18-5.09 (m, 1H), 5.06 (ddt,J=10.1, 2.2, 1.2 Hz, 1H), 4.62 (d, J=11.5 Hz, 1H), 4.55 (d, J=11.5 Hz,1H), 4.00-3.82 (m, 1H), 3.40 (ddd, J=7.3, 5.2, 3.8 Hz, 1H), 2.41 (dtt,J=14.3, 7.1, 1.4 Hz, 1H), 2.33-2.23 (m, 1H), 2.21 (s, 1H), 1.17 (d,J=6.5 Hz, 3H); HRMS-ESI (m/z) ([M+H]⁺) calcd for C₁₃H₁₉O₂, 207.1380;found, 207.1372.

Example 8F: Preparation of (2S,3R)-3-(p-tolyloxy)butan-2-ol

To a solution of4-(((2R,3S)-3-(benzyloxy)butan-2-yl)oxy)-2-chloro-1-methylbenzene (330mg, 1.08 mmol) in EtOH (11 mL) were added NEt₃ (0.30 mL, 2.17 mmol), 10%Pd/C (58 mg, 0.054 mmol), and the reaction vessel was evacuated andback-filled with H₂ (3×). The mixture was stirred under H₂ for 24 h atroom temperature, filtered through a plug of Celite®, and concentratedto provide an oily solid. The residue was suspended in CH₂Cl₂ (20 mL),washed with 1N HCl (20 mL), dried over Na₂SO₄, filtered, andconcentrated to provide 312 mg of a colorless oil, which was dissolvedin a 2:1 mixture of EtOH:cyclohexene (10 mL), treated with 10% Pd/C (58mg, 0.054 mmol), and warmed to and stirred at 65° C. for 20 h. Themixture was cooled to room temperature, filtered through a plug ofCelite®, and concentrated to provide the title compound (188 mg, 96%) asa colorless oil: IR (Thin film) 3391, 2977, 2923, 1613, 1585, 1508,1450, 1373, 1287, 1232, 1167, 1082, 1050, 1008, 993, 935, 901, 813, 746cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.08 (d, J=8.2 Hz, 2H), 6.91-6.68 (m,2H), 4.27 (qd, J=6.3, 3.3 Hz, 1H), 4.02 (dd, J=6.2, 3.3 Hz, 1H), 2.29(s, 3H), 2.07 (s, 1H), 1.25 (d, J=5.6 Hz, 3H), 1.23 (d, J=5.8 Hz, 3H);¹³C NMR (126 MHz, CDCl₃) δ 155.35, 130.51, 130.00, 116.18, 77.60, 69.37,20.48, 17.83, 13.45.

Example 8G: Preparation of(2S,3S,4S)-4-cyclopropyl-3-phenoxy-4-propoxybutan-2-ol

A high pressure steel reactor was charged with a solution of(((1S,2S,3S)-3-(benzyloxy)-1-cyclopropyl-1-propoxybutan-2-yl)oxy)benzene(112 mg, 0.316 mmol) in EtOH (10 mL), 10% Pd/C, Degussa type (17 mg,0.016 mmol), and 3 drops of AcOH, and the reactor was charged with 600psi of H₂ and heated to and vigorously stirred at 50° C. for 14 h. Thereaction mixture was filtered through a plug of Celite®, concentrated,and the residue was diluted with EtOAc and washed with sat. aq. NaHCO₃.The aqueous phase was further extracted with EtOAc and the combinedorganic phases were washed with brine, dried over Na₂SO₄, filtered, andconcentrated to yield the title compound (66.0 mg, 79%) as a colorlessoil: IR (neat) 3448, 2963, 2932, 1597, 1492, 1238, 1079 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 7.31-7.25 (m, 2H), 7.01-6.98 (m, 2H), 6.98-6.93 (m,1H), 4.34-4.25 (m, 1H), 4.20 (dd, J=7.0, 3.3 Hz, 1H), 3.80-3.72 (m, 1H),3.47-3.40 (m, 1H), 3.33 (d, J=4.2 Hz, 1H), 3.11 (dd, J=8.2, 3.3 Hz, 1H),1.66-1.57 (m, 2H), 1.27 (d, J=6.2 Hz, 3H), 1.14-1.04 (m, 1H), 0.93 (t,J=7.4 Hz, 3H), 0.71-0.63 (m, 1H), 0.53-0.45 (m, 1H), 0.45-0.38 (m, 1H),0.26-0.14 (m, 1H); HRMS-ESI (m/z) [M]⁺ calcd for C₁₆H₂₄O₃, 264.1725;found, 264.1723.

Example 9, Step 1: Preparation of(R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropan-1-ol

To a solution of isopropylmagnesium chloride (62 mL, 125 mmol, 2 M inTHF) and lithiumborohydride (LiBH₄; 41 mL, 81 mmol, 2 M in THF) inanhydrous THF (350 mL) at −5° C. was added (R)-methyl2,2-dimethyl-1,3-dioxolane-4-carboxylate (10 g, 62 mmol) dropwise at arate that kept the temperature below 5° C. The reaction mixture wasallowed to warm slowly to room temperature overnight, cooled to 0° C.,and carefully quenched by the addition of H₂O. The phases were separatedand the aq. phase was extracted with Et₂O. The organic phases werecombined, dried over Na₂SO₄, filtered, and concentrated to a colorlessoil, which was purified by flash column chromatography (SiO₂, 0→410%acetone in hexanes) to provide the title compound (5.07 g, 47%) as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 4.21-4.10 (m, 1H), 4.02 (dd,J=8.0, 6.5 Hz, 1H), 3.76 (dd, J=8.0, 7.2 Hz, 1H), 3.23 (dt, J=6.2, 5.3Hz, 1H), 2.13 (d, J=6.3 Hz, 1H), 1.76-1.62 (m, 1H), 1.44 (s, 3H), 1.38(s, 3H), 0.98 (d, J=6.8 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 109.17,76.86, 76.30, 66.55, 31.56, 26.60, 25.44, 19.41, 17.49; ESIMS m/z 174(([M+H]⁺)).

Example 9, Step 2: Preparation of(R)-4-((R)-1-(3-chlorophenoxy)-2-methylpropyl)-2,2-dimethyl-1,3-dioxolane

To a solution of(R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropan-1-ol (5.62 g,32.3 mmol) in anhydrous DMF (32 mL) was added KOt-Bu (4.34 g, 38.7 mmol)in one portion, and the reaction mixture was stirred for 5 min at roomtemperature, treated with 1-chloro-3-fluorobenzene (10.3 mL, 97 mmol),and heated to and stirred at 55° C. for about 3 h. To the mixture wereadded additional KOt-Bu (1.8 g, 16.1 mmol) and 1-chloro-3-fluorobenzene(3.45 mL, 32.3 mmol) and stirring at 55° C. was continued until thinlayer chromatography (TLC) indicated full consumption of the startingmaterial. The reaction mixture was partitioned between Et₂O and H₂O andthe phases were separated. The organic phase was washed with H₂O (2×),dried over Na₂SO₄, filtered, and evaporated. The crude material waspurified by flash column chromatography (SiO₂, 0→5% acetone in hexanes)to provide the title compound (8.97 g, 98%) as a colorless oil: ¹H NMR(400 MHz, CDCl₃) δ 7.16 (t, J=8.2 Hz, 1H), 7.03 (t, J=2.2 Hz, 1H),6.93-6.86 (m, 2H), 4.37 (dt, J=7.6, 6.4 Hz, 1H), 4.07-4.00 (m, 2H), 3.68(t, J=7.9 Hz, 1H), 1.98-1.85 (m, 1H), 1.45 (s, 3H), 1.37 (s, 3H), 1.01(d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ160.96, 134.64, 130.08, 121.03, 116.81, 114.66, 109.40, 83.92, 65.99,30.69, 26.41, 25.58, 19.84, 17.35; EIMS m/z 284.

Example 9, Step 3: Preparation of(R)-2,2-dimethyl-4-((R)-2-methyl-1-phenoxypropyl)-1,3-dioxolane

To a solution of(R)-4-((R)-1-(3-chlorophenoxy)-2-methylpropyl)-2,2-dimethyl-1,3-dioxolane(9.44 g, 33.1 mmol) in absolute ethanol (95 mL) were added 5% Pd/C (3.53g, 1.66 mmol) and NEt₃ (13.1 mL, 99 mmol) and H₂ was bubbled through thesolution for several minutes. The reaction mixture was placed underapproximately 1 atmosphere (Atm) of H₂ (balloon) and stirred at roomtemperature overnight. The mixture was filtered through Celite®, rinsingwith Et₂O and the filtrate was washed with aq. 0.1 N HCl (3×), driedover Na₂SO₄, filtered, and evaporated to provide the title compound(7.12 g, 86%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.22(m, 2H), 7.00 (dt, J=7.9, 1.1 Hz, 2H), 6.92 (tt, J=7.3, 1.1 Hz, 1H),4.39 (dt, J=7.8, 6.1 Hz, 1H), 4.09-3.98 (m, 2H), 3.71 (t, J=8.0 Hz, 1H),2.01-1.91 (m, 1H), 1.45 (s, 3H), 1.37 (s, 3H), 1.03 (d, J=6.9 Hz, 3H),1.00 (d, J=6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 160.19, 129.35,120.85, 116.27, 109.23, 83.12, 65.99, 30.74, 26.43, 25.67, 19.83, 17.76;EIMS m/z 250.

Example 10, Step 1: Preparation of(2R,3R)-4-methyl-3-phenoxypentane-1,2-diol

To a solution of(R)-2,2-dimethyl-4-((R)-2-methyl-1-phenoxypropyl)-1,3-dioxolane (7.1 g,28.4 mmol) in THF (50 mL) was added aq. 1 N HCl (50 mL) and the reactionmixture was stirred vigorously overnight and diluted with Et₂O. Thephases were separated and the aq. phase was extracted with Et₂O. Thecombined organic phases were then washed sequentially with sat. aq.NaHCO₃ and brine, dried over Na₂SO₄, filtered, and evaporated. The cruderesidue was purified by flash column chromatography (SiO₂, 0→50% acetonein hexanes) to provide the title compound (5.44 g, 91%) as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.20 (m, 2H), 6.99-6.90 (m, 3H),4.14 (dd, J=5.8, 4.3 Hz, 1H), 3.97-3.88 (m, 1H), 3.68-3.55 (m, 2H), 2.71(d, J=6.4 Hz, 1H), 2.51 (t, J=5.8 Hz, 1H), 2.15-2.04 (m, 1H), 0.99 (d,J=6.8, 1.6 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 159.62, 129.63, 121.25,115.99, 82.58, 72.12, 64.12, 30.01, 19.44, 18.03; EIMS m/z 210.

Example 10, Steps 2, 3a and 3b: Preparation of(R)-3-methyl-2-phenoxybutan-1-ol and(3S,4R)-5-methyl-4-phenoxyhexan-3-ol

Step 2:

To a solution of (2R,3R)-4-methyl-3-phenoxypentane-1,2-diol (0.5 g, 2.38mmol) in CH₂Cl₂ (4 mL) and sat. aq. NaHCO₃ (1 mL) was added sodiumperiodate (2.034 g, 9.51 mmol) and the mixture was stirred vigorouslyuntil TLC showed full consumption of the diol. The reaction mixture wasfiltered and the filtrate was washed with H₂O, dried over Na₂SO₄,filtered, and concentrated to give the intermediate aldehyde,(R)-3-methyl-2-phenoxybutanal, which was used without furtherpurification.

Step 3a:

To a solution of crude (R)-3-methyl-2-phenoxybutanal (˜1 mmol) in MeOH(3.3 mL) was added NaBH₄ (76 mg, 2.0 mmol) in one portion and themixture was stirred until TLC showed full consumption of the aldehyde.The reaction mixture was cautiously quenched with sat. aq. NH₄Cl (10mL), diluted with CH₂Cl₂, and the phases were separated. The aq. phasewas extracted with CH₂Cl₂ (2×) and the combined organic phases weredried by passing through a phase separator cartridge. The solvent wasevaporated and the resulting crude material was purified by flash columnchromatography (SiO₂, 0→15% acetone in hexanes) to provide the titlecompound (170 mg, 94%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ7.32-7.24 (m, 2H), 7.00-6.91 (m, 3H), 4.15 (td, J=6.1, 3.6 Hz, 1H),3.88-3.73 (m, 2H), 2.14-2.01 (m, 1H), 1.80 (dd, J=7.3, 5.6 Hz, 1H), 1.01(d, J=6.9 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ158.86, 129.57, 121.18, 116.35, 83.94, 62.27, 29.25, 18.62, 18.09; ESIMSm/z 181 (([M+H]⁺)).

Step 3b:

To a solution of ethylmagnesium bromide (EtMgBr; 3.99 mL, 4 mmol, 1 M inTHF) in THF at −78° C. was added a solution of crude(R)-3-methyl-2-phenoxybutanal (˜2 mmol) in THF (6 mL), and the mixturewas stirred until TLC showed full consumption of the aldehyde. Thereaction mixture was cautiously quenched with sat. aq. NH₄Cl, dilutedwith Et₂O, and the phases were separated. The aq. phase was extractedwith Et₂O, and the combined organic phases were dried over Na₂SO₄,filtered, and concentrated. The crude residue was purified by flashcolumn chromatography (SiO₂, 0→10% acetone in hexanes) to provide thetitle compound (187 mg, 45%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃)δ 7.29-7.22 (m, 2H), 7.00-6.96 (m, 2H), 6.95-6.89 (m, 1H), 4.11 (t,J=5.3 Hz, 1H), 3.80-3.71 (m, 1H), 2.15-2.03 (m, 1H), 1.76-1.64 (m, 1H),1.57 (d, J=4.5 Hz, 1H), 1.49 (ddd, J=14.3, 9.6, 7.2 Hz, 1H), 1.02 (d,J=6.8 Hz, 3H), 1.01 (t, J=7.5 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H); ¹³C NMR(101 MHz, CDCl₃) δ 160.03, 129.50, 120.80, 116.01, 85.65, 73.83, 29.86,25.33, 19.88, 18.19, 10.36; EIMS m/z 208.

Example 11, Step 1: Preparation of (R)-methyl3-methyl-2-phenoxybutanoate

To a solution of(S)-2,2-dimethyl-4-((R)-2-methyl-1-phenoxypropyl)-1,3-dioxolane (1.45 g,5.79 mmol) in a mixture of CH₃CN (17 mL), carbon tetrachloride (CCl₄; 17mL) and H₂O (25 mL) was added orthoperiodic acid (H₅IO₆; 6.60 g, 29.0mmol), and the resulting colorless mixture was stirred vigorously for 26h, treated with ruthenium(III) chloride (RuCl₃; 0.024 g, 0.12 mmol), andstirred vigorously for 80 min. The reaction mixture was cooled to 0° C.,quenched by the addition of sat. aq. NaHSO₃ (100 mL), and diluted withEtOAc (150 mL). The phases were separated and the organic phase waswashed with brine (100 mL), dried over MgSO₄, filtered, and concentratedto a yellow oil, which was dissolved in a mixture of MeOH (8 mL) andbenzene (22 mL). The resulting solution was treated withtrimethylsilyldiazomethane (5.79 mL, 11.6 mmol, 2 M in Et₂O) and thereaction mixture was stirred at room temperature for 30 min. The solventand volatile components were evaporated to give a yellow oil which waspurified by flash column chromatography (SiO₂, 1→4% ethyl acetate inhexanes) to provide the title compound (671 mg, 56%) as a colorless oil:¹H NMR (400 MHz, CDCl₃) δ 7.33-7.19 (m, 2H), 7.03-6.93 (m, 1H),6.93-6.81 (m, 2H), 4.38 (d, J=5.6 Hz, 1H), 3.74 (s, 3H), 2.41-2.19 (m,1H), 1.09 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.9 Hz, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 171.91, 158.23, 129.54, 121.49, 115.07, 81.63, 51.99, 31.71,18.62, 17.85; ESIMS m/z 209 (([M+H]⁺)).

Example 11, Step 2: Preparation of (R)-2,4-dimethyl-3-phenoxypentan-2-ol

To a solution of (R)-methyl 3-methyl-2-phenoxybutanoate (671 mg, 3.22mmol) in anhydrous Et₂O (16 mL) was added methylmagnesium bromide (3.22mL, 9.67 mmol, 3 M in Et₂O) at 0° C., and the flask was removed from thecooling bath and warmed to room temperature. After 2 h, the reactionmixture was quenched by adding H₂O (20 mL), diluted with EtOAc (20 mL),and the mixture treated with 2 M HCl until the mixture became clear andbiphasic. The phases were separated and the aq. phase was extracted withEtOAc (2×20 mL). The organic phases were combined, dried over MgSO₄,filtered, and evaporated to give an oil, which was purified by flashcolumn chromatography (SiO₂, 2410% acetone in hexanes) to afford thetitle compound (526 mg, 78%) as a clear, colorless oil: ¹H NMR (400 MHz,CDCl₃) δ 7.32-7.22 (m, 2H), 7.03-6.95 (m, 2H), 6.95-6.88 (m, 1H), 4.05(d, J=3.4 Hz, 1H), 2.17 (s, 1H), 2.13 (ddp, J=10.3, 6.9, 3.4 Hz, 1H),1.29 (s, 3H), 1.26 (s, 3H), 1.05 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.9 Hz,3H); ¹³C NMR (101 MHz, CDCl₃) δ 160.53, 129.52, 120.78, 115.80, 87.85,73.82, 29.86, 27.90, 25.53, 22.79, 17.62; ESIMS m/z 209 (([M+H]⁺)).

Example 12A: Preparation of(S)-(1R,2S)-1-cyclopentyl-1-(cyclopropylmethoxy)-propan-2-yl-2-((tert-butoxycarbonyl)amino)propanoate(Cmpd 737)

To a solution of (1R,2S)-1-cyclopentyl-1-(cyclopropylmethoxy)propan-2-ol(160 mg, 0.807 mmol) in CH₂Cl₂ (4.0 mL) were added(S)-2-((tert-butoxycarbonyl)amino)propanoic acid (Boc-Ala-OH; 168 mg,0.888 mmol) and DMAP (9.86 mg, 0.081 mmol), followed byN¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (EDC; 309 mg, 1.61 mmol), and the reaction mixture wasstirred at room temperature overnight and then concentrated to give ayellow oil. The crude material was purified by flash columnchromatography (SiO₂, 1→12% acetone in hexanes) to afford the titlecompound (189 mg, 63%) as a colorless oil: IR (Thin film) 3362, 2951,2869, 1714, 1500, 1451 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.10-4.96 (m,2H), 4.34-4.22 (m, 1H), 3.54 (dd, J=9.8, 7.0 Hz, 1H), 3.30 (dd, J=9.8,6.8 Hz, 1H), 3.16 (dd, J=8.4, 2.5 Hz, 1H), 1.95-1.81 (m, 3H), 1.71-1.59(m, 3H), 1.57-1.49 (m, 3H), 1.45 (s, 9H), 1.38 (d, J=7.2 Hz, 3H), 1.26(d, J=6.6 Hz, 3H), 1.12-1.01 (m, 1H), 0.56-0.46 (m, 2H), 0.24-0.17 (m,2H); ESIMS m/z 370 (([M+H]⁺)).

Example 12B: Preparation of(R)-2,4-dimethyl-3-phenoxypentan-2-yl-2-((tert-butoxycarbonyl)amino)propanoate(Cmpd 728)

To a solution of (R)-2,4-dimethyl-3-phenoxypentan-2-ol (480 mg, 2.30mmol), DMAP (845 mg, 6.91 mmol), Sc(OTf)₃ (680 mg, 1.38 mmol), andBoc-Ala-OH (1.31 g, 6.91 mmol) in CH₂Cl₂ (23 mL) at 0° C. was addedN,N-methanediylidenebis(propan-2-amine) (DIC; 1.12 mL, 7.26 mmol), andthe reaction mixture was heated to and stirred at reflux for 8 h, cooledto room temperature, and stirred for an additional 24 h. The mixture wasfiltered through a plug of Celite® and the filtrate was washed with 0.1N HCl (30 mL), dried over Na₂SO₄, filtered, and evaporated to provide a1:1 mixture of diastereomers of the title compound (219 mg, 24%) as acolorless oil: ¹H NMR (400 MHz, CDCl₃) for one diastereomer δ 7.33-7.17(m, 2H), 7.03-6.82 (m, 3H), 4.86 (s, 1H), 4.64 (dd, J=16.5, 4.4 Hz, 1H),4.20-3.90 (m, 1H), 2.18-2.03 (m, 1H), 1.59-1.51 (m, 6H), 1.44 (s, 9H),1.17 (t, J=6.9 Hz, 3H), 1.06 (dd, J=6.9, 1.5 Hz, 3H), 1.01 (dd, J=6.8,1.6 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) for both diasteromers δ 172.48,172.34, 160.23, 160.18, 155.11, 155.04, 129.47, 129.46, 120.69, 120.63,115.70, 115.64, 86.67, 86.45, 84.13, 83.93, 79.61, 79.57, 49.94, 49.85,29.60, 29.54, 28.34, 28.33, 23.56, 23.42, 22.59, 22.56, 22.45, 22.38,18.37, 18.31, 18.30, 18.25; ESIMS m/z 380 (([M+H]⁺)).

Example 13, Step 1: Preparation of(S)-(2S,3R)-3-(benzyloxy)hex-5-en-2-yl-2-((di-tert-butoxycarbonyl)amino)propanoate(Cmpd 34 and Cmpd 131)

To a solution of(S)-(2S,3R)-3-(benzyloxy)hex-5-en-2-yl-2-((tert-butoxycarbonyl)amino)-propanoate(129.6 mg, 0.343 mmol) in CH₃CN (3.4 mL), were added DMAP (62.9 mg,0.515 mmol) and Boc₂O (225 mg, 1.030 mmol), and the resulting paleorange reaction mixture was stirred at room temperature overnight. Themixture was treated with additional DMAP (62.9 mg, 0.515 mmol) and Boc₂O(225 mg, 1.030 mmol) and stirred at room temperature for an additional 2h. The reaction mixture was concentrated to a brown/red oil which waspurified by flash column chromatography (SiO₂, 0→20% EtOAc in hexanes)to afford the title compound (176.6 mg, 97%) as a clear, colorless oil:IR (Thin film) 2981, 2940, 1739, 1696, 1642, 1455 cm¹; ¹H NMR (400 MHz,CDCl₃) δ 7.39-7.22 (m, 10H), 5.90-5.75 (m, 1H), 5.17-4.90 (m, 4H), 4.68(d, J=11.5 Hz, 1H), 4.53 (d, J=11.4 Hz, 1H), 3.58 (ddd, J=7.5, 5.3, 3.3Hz, 1H), 2.39-2.18 (m, 2H), 1.51 (d, J=6.9 Hz, 3H), 1.48 (s, 18H), 1.27(d, J=6.5 Hz, 3H); ESIMS m/z 500 (([M+Na]⁺)).

Example 13, Step 2: Preparation of(S)-(2S,3R)-3-(benzyloxy)-5-hydroxypentan-2-yl-2-((di-tert-butoxycarbonyl)amino)propanoate(SM: Cmpd 131)

To a solution of(S)-(2S,3R)-3-(benzyloxy)hex-5-en-2-yl-2-((di-tert-butoxycarbonyl)-amino)propanoate(154.6 mg, 0.324 mmol) and NaHCO₃ (2.72 mg, 0.032 mmol) in a mixture ofanhydrous CH₂Cl₂ (3.1 mL) and anhydrous MeOH (99 μL) were added 5 dropsof a 1% solution of Sudan III in CH₂Cl₂. The reaction mixture was cooledto −78° C. and O₃ was bubbled through the solution until it became clearand colorless. The mixture was purged with O₂ for several min, purgedwith N₂ for several min, diluted with additional MeOH (1.2 mL), treatedwith a single portion of NaBH₄ (36.7 mg, 0.971 mmol), and the resultingsolution was allowed to warm to room temperature with stirringovernight. The reaction mixture was quenched by the addition of H₂O (20mL) and the phases were separated. The aq. phase was extracted withCH₂Cl₂ (3×20 mL) and the combined organic phases were dried by passingthrough a phase separator cartridge and evaporated to an oil, which waspurified by flash column chromatography (SiO₂, 0→100% EtOAc in hexanes)to afford the title compound (132.6 mg, 81%) as a clear, colorless oil:IR (Thin film) 2981, 1734, 1694, 1455 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.39-7.27 (m, 5H), 5.10 (qd, J=6.5, 2.5 Hz, 1H), 4.98 (q, J=6.9 Hz, 1H),4.77 (d, J=11.3 Hz, 1H), 4.50 (d, J=11.3 Hz, 1H), 3.81-3.63 (m, 3H),2.09 (t, J=5.4 Hz, 1H), 1.82-1.62 (m, 2H), 1.52 (d, J=7.0 Hz, 3H), 1.48(s, 18H), 1.27 (d, J=6.5 Hz, 3H); HRMS-ESI (m/z) (([M+Na]⁺)) calcd forC₂₅H₃₉NNaO₈, 504.2568; found, 504.2567.

Example 13, Step 3: Preparation of(S)-(2S,3R)-3-(benzyloxy)-5-methoxypentan-2-yl-2-((di-tert-butoxycarbonyl)amino)propanoate(Product: Cmpd 132)

To a solution of(S)-(2S,3R)-3-(benzyloxy)-5-hydroxypentan-2-yl-2-((di-tert-butoxycarbonyl)-amino)propanoate(133 mg, 0.275 mmol) in CH₂Cl₂ (2.76 mL) were added Proton Sponge® (118mg, 0.551 mmol) and trimethyloxonium tetrafluoroborate (52.9 mg, 0.358mmol), and the resulting colorless reaction mixture was stirred at roomtemperature overnight. The resulting cloudy, orange mixture wascarefully quenched by adding sat. aq. NaHCO₃ (20 mL) and the phases wereseparated. The aq. phase was extracted with CH₂Cl₂ (3×20 mL), and thecombined organic phases were washed sequentially with aq. 1 N HCl (2×20mL) and brine, dried by passing through a phase separator cartridge, andevaporated to give an oil, which was purified by flash columnchromatography (SiO₂, 0→50% EtOAc in hexanes) to afford the titlecompound (113 mg, 79%) as a clear, colorless oil: IR (Thin film) 2980,2936, 1739, 1696, 1455 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.20 (m,5H), 5.07 (qd, J=6.5, 2.6 Hz, 1H), 4.97 (q, J=6.9 Hz, 1H), 4.73 (d,J=11.3 Hz, 1H), 4.46 (d, J=11.3 Hz, 1H), 3.69 (ddd, J=8.7, 4.3, 2.6 Hz,1H), 3.52-3.39 (m, 2H), 3.28 (s, 3H), 1.80-1.65 (m, 2H), 1.52 (d, J=6.9Hz, 3H), 1.48 (s, 18H), 1.25 (d, J=6.5 Hz, 3H); HRMS-ESI (m/z) ([M+Na]⁺)calcd for C₂₆H₄₁NNaO₈, 518.2724; found, 518.2718.

Example 14A, Steps 1 and 2: Preparation of(S)-(1R,2S)-1-cyclopentyl-1-(cyclopropyl-methoxy)propan-2-yl-2-(3-hydroxy-4-methoxypicolinamido)propanoate(Cmpd 737, Cmpd 786, and Cmpd 845)

Step 1:

To a solution of(S)-(1R,2S)-1-cyclopentyl-1-(cyclopropylmethoxy)propan-2-yl-2-((tert-butoxycarbonyl)amino)propanoate(189 mg, 0.512 mmol) in CH₂Cl₂ (3.4 mL) was added a 4 N solution of HClin dioxane (2.6 mL, 10.2 mmol), and the mixture was stirred for 3 h atroom temperature. The solvent was evaporated under a stream of N₂ toprovide the intermediate amine hydrochloride,(S)-1-(((1R,2S)-1-cyclopentyl-1-(cyclopropylmethoxy)propan-2-yl)oxy)-1-oxopropan-2-aminiumchloride, as a white solid: ESIMS m/z 340 ([M+H]⁺).

Step 2:

To a solution of(S)-1-(((1R,2S)-1-cyclopentyl-1-(cyclopropylmethoxy)propan-2-yl)oxy)-1-oxopropan-2-aminiumchloride and 3-hydroxy-4-methoxypicolinic acid (95.0 mg, 0.563 mmol) inCH₂Cl₂ (3.4 mL) were added N-ethyl-N-isopropylpropan-2-amine (294 μL,1.69 mmol) and PyBOP (293 mg, 0.563 mmol), and the reaction mixture wasstirred for 4 h at room temperature. The solvent was evaporated and thecrude oil was purified by flash column chromatography (SiO₂, 1→50%acetone in hexanes) to afford the title compound (118 mg, 55%) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 12.13 (d, J=0.6 Hz, 1H), 8.47 (d,J=7.9 Hz, 1H), 7.99 (d, J=5.2 Hz, 1H), 6.88 (dd, J=5.3, 0.6 Hz, 1H),5.09 (qd, J=6.5, 2.3 Hz, 1H), 4.78-4.66 (m, 1H), 3.95 (s, 3H), 3.51 (dd,J=9.8, 6.9 Hz, 1H), 3.23 (dd, J=9.9, 6.8 Hz, 1H), 3.17 (dd, J=8.5, 2.3Hz, 1H), 2.01-1.72 (m, 2H), 1.75-1.45 (m, 6H), 1.56 (d, J=7.2 Hz, 3H),1.46-1.29 (m, 1H), 1.28 (d, J=6.6 Hz, 3H), 1.11-0.96 (m, 1H), 0.55-0.41(m, 2H), 0.15-0.06 (m, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 171.45, 168.69,155.40, 148.77, 140.50, 130.42, 109.46, 85.27, 77.27, 75.19, 56.09,48.12, 42.50, 30.03, 29.15, 25.44, 25.11, 18.21, 13.72, 11.11, 2.87,2.84; HRMS-ESI (m/z) ([M+H]⁺) calcd for C₂₂H₃₃N₂O₆, 421.2333; found,421.2331.

Example 14B, Steps 1 and 2: Preparationof(S)-(2S,3R)-3-(benzyloxy)hex-5-en-2-yl-2-(3-hydroxy-4-methoxypicolinamido)propanoate(Cmpd 34, Cmpd 180, and Cmpd 333)

Step 1:

To a solution of(S)-(2S,3R)-3-(benzyloxy)hex-5-en-2-yl-2-((tert-butoxycarbonyl)-amino)propanoate(182 mg, 0.483 mmol) in CH₂Cl₂ (1.6 mL) at 0° C. was added2,2,2-trifluoroacetic acid (TFA; 400 μL, 5.19 mmol) dropwise over 30seconds, and the resulting orange mixture was warmed to and stirred atroom temperature for 2 h. The reaction mixture was diluted with CH₂Cl₂(5 mL), washed with sat. aq. NaHCO₃ (5 mL), and the phases wereseparated. The aq. phase was extracted with CH₂Cl₂ (3×5 mL), and thecombined organic layers were dried by passing through a phase separatorcartridge and concentrated to afford the intermediate amine,(S)-(2S,3R)-3-(benzyloxy)hex-5-en-2-yl-2-aminopropanoate (135 mg, 100%),as a clear, colorless oil, which was used directly in the next step:HRMS-ESI (m/z) ([M+H]⁺) calcd for C₁₆H₂₄NO₃, 278.1751; found, 278.1752.

Step 2:

To a solution of(S)-(2S,3R)-3-(benzyloxy)hex-5-en-2-yl-2-aminopropanoate (135 mg, 0.487mmol), 3-hydroxy-4-methoxypicolinic acid (99 mg, 0.584 mmol), and PYBOP(304 mg, 0.584 mmol) in CH₂Cl₂ (4.87 mL) was addedN-ethyl-N-isopropylpropan-2-amine (305 μL, 1.75 mmol) dropwise over a 45second (sec) period, and the reaction mixture was stirred at roomtemperature overnight. The mixture was concentrated and the resultingorange/brown oil was purified by flash column chromatography (SiO₂,0→50% acetone in hexanes) to afford the title compound (212 mg, 86%) asa clear, colorless oil: IR (Thin film) 3369, 3063, 2981, 2940, 2877,1737, 1648, 1576, 1528, 1481, 1452, 1438 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ12.12 (d, J=0.6 Hz, 1H), 8.49 (d, J=7.9 Hz, 1H), 7.94 (d, J=5.2 Hz, 1H),7.38-7.19 (m, 5H), 6.83 (dd, J=5.2, 2.6 Hz, 1H), 5.84 (ddt, J=17.2,10.2, 7.0 Hz, 1H), 5.20-5.00 (m, 3H), 4.79-4.66 (m, 1H), 4.62 (d, J=11.5Hz, 1H), 4.52 (d, J=11.5 Hz, 1H), 3.92 (s, 3H), 3.57 (ddd, J=7.2, 5.3,3.5 Hz, 1H), 2.42-2.24 (m, 2H), 1.54 (d, J=7.2 Hz, 3H), 1.31 (d, J=6.5Hz, 3H); HRMS-ESI (m/z) ([M+H]⁺) calcd for C₂₃H₂₉N₂O₆, 429.2020; found,429.2025.

Example 14C, Steps 1 and 2: Preparation of(S)-(2S,3R,4R)-4-benzyl-3-isobutoxyhexan-2-yl-2-(3-hydroxy-4-methoxypicolinamido)propanoate(Cmpd 4, Cmpd 146, and Cmpd 293)

Step 1:

To a solution of(S)-(2S,3R,4R)-4-benzyl-3-isobutoxyhexan-2-yl-2-((((9H-fluoren-9-yl)methoxy)-carbonyl)amino)propanoate(350 mg, 0.63 mmol) in THF (6 mL) was added morpholine (0.63 mL, 7.2mmol) and the resulting solution was stirred at room temperature for 4d. The mixture was filtered and the filtrate was evaporated to give asticky, white solid, which was purified by reverse phase columnchromatography (C₁₈, CH₃CN in H₂O, NaOAc buffer) to afford theintermediate aminium acetate,1-(((2S,3R,4R)-4-benzyl-3-isobutoxyhexan-2-yl)oxy)-1-oxopropan-2-aminiumacetate. The aminium acetate was dissolved in EtOAc (10 mL), washed withsat. aq. NaHCO₃, and the phases were separated. The organic phase wasdried over Na₂SO₄, filtered, and concentrated to give the intermediateamine, (2S,3R,4R)-4-benzyl-3-isobutoxyhexan-2-yl-2-aminopropanoate (90mg, 43%, 1.5:1 mixture of diastereomers at the amine bearing carbon), asa colorless oil: ¹H NMR (400 MHz, CDCl₃) for both diastereomers δ7.31-7.22 (m, 2H), 7.21-7.12 (m, 3H), 5.22-5.09 (m, 1H), 3.52 (adq,J=8.9, 7.0 Hz, 1H), 3.42 (atd, J=8.5, 6.4 Hz, 1H), 3.30 (at, J=4.9 Hz,1H), 3.24 (addd, J=8.4, 6.4, 4.3 Hz, 1H), 2.98 (adt, J=13.8, 3.8 Hz,1H), 2.43 (addd, J=13.6, 9.9, 2.6 Hz, 1H), 1.92-1.81 (m, 1H), 1.72 (adp,J=15.7, 5.1 Hz, 1H), 1.58 (bs, 2H), 1.40-1.24 (m, 2H), 1.34 (ad, J=7.0Hz, 3H), 1.31-1.27 (m, 3H), 0.94 (ad, J=6.7 Hz, 6H), 0.87 (atd, J=7.5,3.1 Hz, 3H).

Step 2:

To a suspension of(2S,3R,4R)-4-benzyl-3-isobutoxyhexan-2-yl-2-aminopropanoate (0.09 g,0.268 mmol), 3-hydroxy-4-methoxypicolinic acid (0.05 g, 0.295 mmol), andPYBOP (0.209 g, 0.402 mmol) in CH₂Cl₂ (1.5 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.141 mL, 0.805 mmol), and theresulting dark brown solution was stirred at room temperature for 48 hThe reaction mixture was partitioned between EtOAc and aq. 1 N HCl, andthe phases were separated. The organic phase was washed with sat. aq.NaHCO₃, dried over Na₂SO₄, filtered, and concentrated. The resultingcrude residue was purified by flash column chromatography (SiO₂, 30%EtOAc in hexanes) to afford a 1.5:1 mixture of diastereomers (at theamine bearing carbon) of the title compound (125 mg, 96%) as a colorlessoil: ¹H NMR (400 MHz, CDCl₃) for both diastereomers δ 12.15 (add,J=11.4, 0.5 Hz, 1H), 8.49 (at, J=8.0 Hz, 1H), 7.97 (add, J=5.2, 3.5 Hz,1H), 7.31-7.19 (m, 2H), 7.15 (m, 3H), 6.86 (ad, J=5.1 Hz, 1H), 5.25-5.16(m, 1H), 4.76-4.66 (m, 1H), 3.94 (s, 3H), 3.42 (add, J=8.5, 6.4 Hz, 1H),3.33 (aq, J=5.0 Hz, 1H), 3.22 (addd, J=17.7, 8.5, 6.4 Hz, 1H), 2.97(add, J=13.8, 4.3 Hz, 1H), 2.42 (addd, J=13.6, 10.0, 3.2 Hz, 1H),1.89-1.77 (m, 1H), 1.73 (apptt, J=10.2, 4.8 Hz, 1H), 1.56 (d, J=7.2 Hz,3H), 1.39-1.25 (m, 2H), 1.37-1.22 (m, 3H), 0.96-0.81 (m, 9H); ¹³C NMR(101 MHz, CDCl₃) for both diastereomers δ 171.51, 171.44, 168.76,168.70, 155.38, 155.37, 148.77, 141.54, 141.53, 140.50, 130.43, 129.14,128.19, 128.17, 125.66, 125.64, 109.46, 81.72, 79.54, 79.50, 73.20,73.19, 56.08, 48.10, 48.01, 43.62, 43.55, 35.39, 29.20, 22.18, 22.00,19.51, 19.46, 18.32, 18.23, 15.54, 15.30, 10.82, 10.63; ESIMS m/z 487(([M+H]⁺)).

Example 14D, Steps 1 and 2: Preparation of(R)-2,4-dimethyl-3-phenoxypentan-2-yl2-(3-hydroxy-4-methoxypicolinamido)propanoate (Cmpd 728, Cmpd 779, andCmpd 835)

Step 1:

To a solution of (R)-2,4-dimethyl-3-phenoxypentan-2-yl2-((tert-butoxycarbonyl)amino)propanoate (197 mg, 0.519 mmol) inanhydrous CH₂Cl₂ (5 mL) was added 2,6-lutidine (302 μL, 2.60 mmol)followed by trimethylsilyl trifluoromethanesulfonate (281 μL, 1.56mmol), and the resulting solution was stirred at room temperature for 4h. The reaction mixture was diluted with MeOH (2.5 mL) and the resultingsolution was stirred at room temperature for 30 min and concentrated togive the intermediate amine salt, (R)-2,4-dimethyl-3-phenoxypentan-2-yl2-aminopropanoate trifluoromethanesulfonate (223 mg, 100%) as a yellowoil: ESIMS m/z 280.4 (([M+H]⁺)).

Step 2:

To a solution of (R)-2,4-dimethyl-3-phenoxypentan-2-yl 2-aminopropanoatetrifluoromethanesulfonate (223 mg, 0.519 mmol) in anhydrous CH₂Cl₂ (5mL) were added 3-hydroxy-4-methoxypicolinic acid (97 mg, 0.57 mmol),PyBOP (297 mg, 0.571 mmol), and Hunig's base (299 μL, 1.71 mmol), andthe resulting mixture was stirred at room temperature for 2 h,concentrated, and the residue purified by column chromatography (SiO₂;4→40% acetone in hexanes) to provide the title compound (24 mg, 11%) asan oil: ¹H NMR (400 MHz, CDCl₃) δ 12.18 (d, J=3.7 Hz, 1H), 8.40 (d,J=7.6 Hz, 1H), 7.99 (d, J=5.0 Hz, 1H), 7.26-7.17 (m, 2H), 6.96 (dd,J=7.8, 4.9 Hz, 2H), 6.92-6.80 (m, 2H), 4.67 (dd, J=19.2, 4.4 Hz, 1H),4.47 (dp, J=29.2, 7.2 Hz, 1H), 3.94 (s, 3H), 2.12 (ddt, J=13.8, 6.9, 3.3Hz, 1H), 1.62-1.54 (m, 6H), 1.38-1.31 (m, 3H), 1.06 (dd, J=6.9, 2.2 Hz,3H), 1.01 (d, J=6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 171.32, 171.28,168.62, 168.55, 160.11, 155.36, 148.73, 148.71, 140.47, 130.55, 129.48,120.75, 120.66, 115.72, 115.58, 109.41, 87.27, 86.97, 84.10, 83.64,56.07, 48.53, 48.44, 29.71, 29.60, 23.77, 23.46, 22.65, 22.43, 22.29,18.33, 18.26, 18.01, 17.92; HRMS-ESI (m/z) ([M+H]⁺) calcd forC₂₃H₃₁N₂O₆, 431.2177; found, 431.2187.

Example 15: Preparation of(S)-(1R,2S)-1-cyclopentyl-1-(p-tolyloxy)propan-2-yl-2-(3-hydroxy-4-methoxypicolinamido)propanoate(Cmpd 843 and Cmpd 846)

A suspension of(S)-(1R,2S)-1-(2-chloro-4-methylphenoxy)-1-cyclopentylpropan-2-yl-2-(3-hydroxy-4-methoxypicolinamido)propanoate(202 mg, 0.411 mmol), 5% Pd/C (88 mg, 0.041 mmol), and NEt₃ (172 μL,1.234 mmol) in EtOH (8.2 mL) was stirred under approximately 1 Atm(balloon) of H₂ at room temperature for 72 h. The reaction mixture wasfiltered through a pad of Celite® and the filtrate was concentrated togive an oil, which was purified by flash column chromatography (SiO₂,1→30% acetone in hexanes) to afford the title compound (166 mg, 88%) asa white foam: ¹H NMR (400 MHz, CDCl₃) δ 12.11 (d, J=0.6 Hz, 1H), 8.38(d, J=8.1 Hz, 1H), 7.96 (d, J=5.2 Hz, 1H), 7.01-6.96 (m, 2H), 6.86 (d,J=5.4 Hz, 1H), 6.81 (d, J=8.5 Hz, 2H), 5.15 (qd, J=6.5, 3.0 Hz, 1H),4.64-4.49 (m, 1H), 4.28 (dd, J=8.2, 3.0 Hz, 1H), 3.94 (s, 3H), 2.24 (s,3H), 2.18-2.04 (m, 1H), 1.91-1.78 (m, 1H), 1.78-1.64 (m, 2H), 1.62-1.40(m, 5H), 1.37 (d, J=6.5 Hz, 3H), 1.24 (d, J=7.3 Hz, 3H); ¹³C NMR (101MHz, CDCl₃) δ 171.62, 168.64, 157.82, 155.35, 148.73, 140.43, 130.46,130.34, 129.84, 116.30, 109.40, 83.42, 74.16, 56.07, 47.99, 42.21,29.65, 29.01, 25.43, 25.10, 20.44, 17.67, 14.26; HRMS-ESI (m/z) ([M+H]⁺)calcd for C₂₅H₃₃N₂O₆, 457.2333; found, 457.2335.

Example 16A: Preparation of(S)-(1R,2S)-1-(3-chlorophenoxy)-1-cyclopentylpropan-2-yl-2-(3-acetoxy-4-methoxypicolinamido)propanoate(Cmpd 841 and Cmpd 920)

To a solution of(S)-(1R,2S)-1-(3-chlorophenoxy)-1-cyclopentylpropan-2-yl-2-(3-hydroxy-4-methoxypicolinamido)propanoate(100 mg, 0.210 mmol), NEt₃ (58.1 μL, 0.419 mmol), and DMAP (5.12 mg,0.042 mmol) in CH₂Cl₂ (2.1 mL) was added acetyl chloride (22.4 μL, 0.314mmol) at room temperature, and the reaction mixture was stirredovernight. The solvent was evaporated, and the resulting crude oil waspurified by flash column chromatography (SiO₂, 1→40% acetone in hexanes)to afford the title compound (76 mg, 70%) as a colorless oil: ¹H NMR(500 MHz, CDCl₃) δ 8.42 (d, J=8.0 Hz, 1H), 8.30 (d, J=5.4 Hz, 1H), 7.10(t, J=8.2 Hz, 1H), 7.01-6.96 (m, 1H), 6.93 (t, J=2.2 Hz, 1H), 6.85 (ddd,J=7.9, 1.9, 0.9 Hz, 1H), 6.80 (ddd, J=8.4, 2.5, 0.9 Hz, 1H), 5.13 (qd,J=6.5, 2.9 Hz, 1H), 4.63-4.54 (m, 1H), 4.31 (dd, J=8.4, 3.0 Hz, 1H),3.91 (s, 3H), 2.39 (s, 3H), 2.16-2.09 (m, 1H), 1.82 (td, J=10.1, 7.6,4.9 Hz, 1H), 1.73 (qd, J=7.5, 3.4 Hz, 1H), 1.69-1.46 (m, 5H), 1.43-1.36(m, 1H), 1.34 (d, J=6.5 Hz, 3H), 1.25 (d, J=7.2 Hz, 3H); ¹³C NMR (126MHz, CDCl₃) δ 172.16, 168.91, 162.37, 160.58, 159.44, 146.65, 141.43,137.49, 134.72, 130.20, 121.15, 116.75, 114.47, 109.73, 83.60, 73.66,56.29, 47.97, 42.12, 29.70, 28.93, 25.40, 25.07, 20.75, 18.01, 14.10;HRMS-ESI (m/z) ([M+H]⁺) calcd for C₂₆H₃₂ClN₂O₇, 519.1893; found,519.1888.

Example 16B: Preparation of(S)-(1R,2S)-1-(3-chlorophenoxy)-1-cyclopentylpropan-2-yl-2-(3-(acetoxymethoxy)-4-methoxypicolinamido)propanoate(Cmpd 841 and Cmpd 911)

To a suspension of(S)-(1R,2S)-1-(3-chlorophenoxy)-1-cyclopentylpropan-2-yl-2-(3-hydroxy-4-methoxypicolinamido)propanoate(100 mg, 0.210 mmol) and K₂CO₃ (58.0 mg, 0.419 mmol) in acetone (2.1 mL)was added bromomethyl acetate (28.8 μL, 0.294 mmol) at room temperature,and the mixture was heated to and stirred at 55° C. for 3 h, cooled toroom temperature, and stirred overnight. The solvent was evaporated andthe resulting crude material was purified by flash column chromatography(SiO₂, 1→40% acetone in hexanes) to afford the title compound (53.9 mg,47%) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) δ 8.29-8.20 (m, 2H),7.11 (t, J=8.1 Hz, 1H), 6.95-6.91 (m, 2H), 6.86 (ddd, J=8.0, 2.0, 0.9Hz, 1H), 6.81 (ddd, J=8.4, 2.5, 0.9 Hz, 1H), 5.73 (s, 2H), 5.17-5.10 (m,1H), 4.64-4.55 (m, 1H), 4.32 (dd, J=8.4, 3.0 Hz, 1H), 3.91 (s, 3H),2.17-2.09 (m, 1H), 2.07 (s, 3H), 1.87-1.79 (m, 1H), 1.78-1.70 (m, 1H),1.70-1.64 (m, 1H), 1.57 (s, 4H), 1.42-1.36 (m, 1H), 1.36 (d, J=6.6 Hz,3H), 1.26 (d, J=7.1 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 172.25, 170.29,162.95, 160.59, 160.27, 145.68, 144.04, 142.35, 134.72, 130.19, 121.15,116.73, 114.53, 109.53, 89.58, 83.63, 73.63, 56.17, 48.18, 42.12, 29.71,28.91, 25.39, 25.05, 20.87, 17.84, 14.10; HRMS-ESI (m/z) ([M+H]⁺) calcdfor C₂₇H₃₄ClN₂O, 549.1998; found, 549.1997.

Example 16C: Preparation of(S)-(2S,3S,4S)-4-phenoxy-3-propoxyhexan-2-yl-2-(3-((2-ethoxyacetoxy)methoxy)-4-methoxypicolinamido)propanoate(Cmpd 326 and Cmpd 512)

To a solution of(S)-(2S,3S,4S)-4-phenoxy-3-propoxyhexan-2-yl-2-(3-hydroxy-4-methoxypicolinamido)propanoate(103 mg, 0.217 mmol) in acetone (2 mL) were added Na₂CO₃ (46.0 mg, 0.434mmol), sodium iodide (NaI; 6.5 mg, 0.043 mmol) and chloromethyl2-ethoxyacetate (49.7 mg, 0.326 mmol), and the mixture was warmed to andstirred at 40° C. for 6 h, cooled to room temperature, and concentrated.The resulting residue was purified by flash column chromatography (SiO₂,2→30% acetone in hexanes) to afford the title compound (41.4 mg, 32%) asa colorless oil: IR (Thin film) 3383, 2973, 2936, 2878, 1774, 1737, 1677cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (d, J=7.8 Hz, 1H), 8.26 (d, J=5.4Hz, 1H), 7.29-7.19 (m, 2H), 6.98-6.89 (m, 4H), 5.82 (d, J=1.0 Hz, 2H),5.16 (qd, J=6.4, 4.2 Hz, 1H), 4.72-4.63 (m, 1H), 4.27-4.17 (m, 1H), 4.10(s, 2H), 3.90 (s, 3H), 3.65-3.47 (m, 5H), 1.88-1.76 (m, 1H), 1.75-1.65(m, 1H), 1.59-1.49 (m, 2H), 1.42 (d, J=7.2 Hz, 3H), 1.36 (d, J=6.4 Hz,3H), 1.23 (t, J=7.0 Hz, 3H), 1.00 (t, J=7.4 Hz, 3H), 0.87 (t, J=7.4 Hz,3H); HRMS-ESI (m/z) ([M+H]⁺) calcd for C₃₀H₄₃N₂O₁₀, 591.2912; found,591.2913.

Example A: Evaluation of Fungicidal Activity: Leaf Blotch of Wheat(Zymoseptoria tritici; Bayer code SEPTTR)

Technical grades of materials were dissolved in acetone, which were thenmixed with nine volumes of water containing 110 ppm Triton X-100. Thefungicide solutions were applied onto wheat seedlings using an automatedbooth sprayer to run-off. All sprayed plants were allowed to air dryprior to further handling. All fungicides were evaluated using theaforementioned method for their activity vs. all target diseases, unlessstated otherwise. Wheat leaf blotch and brown rust activity were alsoevaluated using track spray applications, in which case the fungicideswere formulated as EC formulations, containing 0.1% Trycol 5941 in thespray solutions.

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Zymoseptoria tritici either prior to orafter fungicide treatments. After inoculation the plants were kept in100% relative humidity (one day in a dark dew chamber followed by two tothree days in a lighted dew chamber at 20° C.) to permit spores togerminate and infect the leaf. The plants were then transferred to agreenhouse set at 20° C. for disease to develop. When disease symptomswere fully expressed on the 1^(st) leaves of untreated plants, infectionlevels were assessed on a scale of 0 to 100 percent disease severity.Percent disease control was calculated using the ratio of diseaseseverity on treated plants relative to untreated plants.

Example B: Evaluation of Fungicidal Activity: Wheat Brown Rust (Pucciniatriticina; Synonym: Puccinia recondita f. sp. Tritici; Bayer CodePUCCRT)

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Puccinia triticina either prior to orafter fungicide treatments. After inoculation the plants were kept in adark dew room at 22° C. with 100% relative humidity overnight to permitspores to germinate and infect the leaf. The plants were thentransferred to a greenhouse set at 24° C. for disease to develop.Fungicide formulation, application and disease assessment followed theprocedures as described in the Example A.

Example C: Evaluation of Fungicidal Activity: Wheat Glume Blotch(Leptosphaeria nodorum; Bayer Code LEPTNO)

Wheat plants (variety Yuma) were grown from seed in a greenhouse in 50%mineral soil/50% soil-less Metro mix until the first leaf was fullyemerged, with 7-10 seedlings per pot. These plants were inoculated withan aqueous spore suspension of Leptosphaeria nodorum 24 hr afterfungicide treatments. After inoculation the plants were kept in 100%relative humidity (one day in a dark dew chamber followed by two days ina lighted dew chamber at 20° C.) to permit spores to germinate andinfect the leaf. The plants were then transferred to a greenhouse set at20° C. for disease to develop. Fungicide formulation, application anddisease assessment followed the procedures as described in the ExampleA.

Example D: Evaluation of Fungicidal Activity: Apple Scab (Venturiainaequalis; Bayer Code VENTIN)

Apple seedlings (variety McIntosh) were grown in soil-less Metro mix,with one plant per pot. Seedlings with two expanding young leaves at thetop (older leaves at bottom of the plants were trimmed) were used in thetest. Plants were inoculated with a spore suspension of Venturiainaequalis 24 hr after fungicide treatment and kept in a 22° C. dewchamber with 100% relative humidity for 48 hr, and then moved to agreenhouse set at 20° C. for disease to develop. Fungicide formulation,application and disease assessment on the sprayed leaves followed theprocedures as described in the Example A.

Example E: Evaluation of Fungicidal Activity: Powdery Mildew of Cucumber(Erysiphe cichoracearum; Bayer Code ERYSCI)

Cucumber seedlings (variety Bush Pickle) were grown in soil-less Metromix, with one plant per pot, and used in the test when 12 to 14 daysold. Plants were inoculated with a spore suspension 24 hr followingfungicide treatments. After inoculation the plants remained in thegreenhouse set at 20° C. until disease was fully expressed. Fungicideformulation, application and disease assessment on the sprayed leavesfollowed the procedures as described in the Example A.

Example F: Evaluation of Fungicidal Activity: Leaf Spot of Sugar Beets(Cercospora beticola; Bayer Code CERCBE)

Sugar beet plants (variety HH88) were grown in soil-less Metro mix andtrimmed regularly to maintain a uniform plant size prior to test. Plantswere inoculated with a spore suspension 24 hr after fungicidetreatments. Inoculated plants were kept in a dew chamber at 22° C. for48 hr then incubated in a greenhouse set at 24° C. under a clear plastichood with bottom ventilation until disease symptoms were fullyexpressed. Fungicide formulation, application and disease assessment onthe sprayed leaves followed the procedures as described in the ExampleA.

Example G: Evaluation of Fungicidal Activity: Asian Soybean Rust(Phakopsora pachyrhizi; Bayer Code PHAKPA)

Technical grades of materials were dissolved in acetone, which were thenmixed with nine volumes of water containing 0.011% Tween 20. Thefungicide solutions were applied onto soybean seedlings using anautomated booth sprayer to run-off. All sprayed plants were allowed toair dry prior to further handling.

Soybean plants (variety Williams 82) were grown in soil-less Metro mix,with one plant per pot. Two weeks old seedlings were used for testing.Plants were inoculated either 3 days prior to or 1 day after fungicidetreatments. Plants were incubated for 24 h in a dark dew room at 22° C.and 100% relative humidity then transferred to a growth room at 23° C.for disease to develop. Disease severity was assessed on the sprayedleaves.

Example H: Evaluation of Fungicidal Activity: Barley Scald(Rhyncosporium secalis; Bayer Code RHYNSE)

Barley seedlings (variety Harrington) were propagated in soil-less Metromix, with each pot having 8 to 12 plants, and used in the test whenfirst leaf was fully emerged. Test plants were inoculated by an aqueousspore suspension of Rhyncosporium secalis 24 hr after fungicidetreatments. After inoculation the plants were kept in a dew room at 22°C. with 100% relative humidity for 48 hr. The plants were thentransferred to a greenhouse set at 20° C. for disease to develop.Fungicide formulation, application and disease assessment on the sprayedleaves followed the procedures as described in the Example A.

Example I: Evaluation of Fungicidal Activity: Rice Blast (Pyriculariaoryzae; Bayer Code PYRIOR)

Rice seedlings (variety Japonica) were propagated in soil-less Metromix, with each pot having 8 to 14 plants, and used in the test when 12to 14 days old. Test plants were inoculated with an aqueous sporesuspension of Pyricularia oryzae 24 hr after fungicide treatments. Afterinoculation the plants were kept in a dew room at 22° C. with 100%relative humidity for 48 hr to permit spores to germinate and infect theleaf. The plants were then transferred to a greenhouse set at 24° C. fordisease to develop. Fungicide formulation, application and diseaseassessment on the sprayed leaves followed the procedures as described inthe Example A.

Example J: Evaluation of Fungicidal Activity: Tomato Early Blight(Alternaria solani; Bayer Code ALTESO)

Tomato plants (variety Outdoor Girl) were propagated in soil-less Metromix, with each pot having one plant, and used when 12 to 14 days old.Test plants were inoculated with an aqueous spore suspension ofAlternaria solani 24 hr after fungicide treatments. After inoculationthe plants were kept in a dew room at 22° C. with 100% relative humidityfor 48 h to permit spores to germinate and infect the leaf. The plantswere then transferred to a growth room at 22° C. for disease to develop.Fungicide formulation, application and disease assessment on the sprayedleaves followed the procedures as described in the Example A.

Example K: Evaluation of Fungicidal Activity: Cucumber Anthracnose(Colletotrichum lagenarium; Bayer Code COLLLA)

Cucumber seedlings (variety Bush Pickle) were propagated in soil-lessMetro mix, with each pot having one plant, and used in the test when 12to 14 days old. Test plants were inoculated with an aqueous sporesuspension of Colletotrichum lagenarium 24 hr after fungicidetreatments. After inoculation the plants were kept in a dew room at 22°C. with 100% relative humidity for 48 hr to permit spores to germinateand infect the leaf. The plants were then transferred to a growth roomset at 22° C. for disease to develop. Fungicide formulation, applicationand disease assessment on the sprayed leaves followed the procedures asdescribed in the Example A.

Lengthy table referenced here US20180000085A1-20180104-T00001 Pleaserefer to the end of the specification for access instructions.

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LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20180000085A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A composition for the control of a fungal pathogen including mixturesof at least one of the compounds of Formula 1

wherein: X is hydrogen or C(O)R₅; Y is hydrogen, C(O)R₅, or Q; Q is

R₁ and R₁₁ are independently chosen from hydrogen or alkyl, optionallysubstituted with 0, 1 or multiple R₈; Alternatively, R₁ and R₁₁ may betaken together to form a 3-6 membered saturated or partially saturatedcarbocycle or heterocycle, optionally substituted with 0, 1 or multipleR₈; R₂ and R₁₂ are independently chosen from hydrogen, alkyl, aryl, oralkenyl, each optionally substituted with 0, 1 or multiple R₈; R₃ ischosen from hydrogen, C₂-C₆ alkyl, aryl, or alkenyl, each optionallysubstituted with 0, 1 or multiple R₈; R₄ is chosen from alkyl, aryl, oracyl, each optionally substituted with 0, 1 or multiple R₅; R₅ is chosenfrom alkoxy or benzyloxy, each optionally substituted with 0, 1, ormultiple R₈; R₆ is chosen from hydrogen, alkoxy, or halo, eachoptionally substituted with 0, 1, or multiple R₈; R₇ is chosen fromhydrogen, —C(O)R₉, or —CH₂OC(O)R₉; R₈ is chosen from hydrogen, alkyl,aryl, acyl, halo, alkenyl, alkoxy, or heterocyclyl, each optionallysubstituted with 0, 1, or multiple R₁₀; R₉ is chosen from alkyl, alkoxy,or aryl, each optionally substituted with 0, 1, or multiple R₈; and R₁₀is chosen from hydrogen, alkyl, aryl, acyl, halo, alkenyl, alkoxy, orheterocyclyl.
 2. The composition according to claim 1, wherein X ishydrogen and Y is Q.
 3. The composition according to claim 2, wherein R₆is alkoxy.
 4. The composition according to claim 3, wherein R₇ ishydrogen.
 5. The composition according to claim 4, wherein R₁ and R₁₁are independently chosen from hydrogen or alkyl.
 6. The compositionaccording to claim 4, wherein R₂ and R₁₂ are independently chosen fromhydrogen or alkyl.
 7. The composition according to claim 4, wherein R₃is chosen from C₂-C₆ alkyl, aryl, or alkenyl, each optionallysubstituted with 0, 1 or multiple R₈.
 8. The composition according toclaim 4, wherein R₄ is chosen from alkyl or aryl, each optionallysubstituted with 0, 1 or multiple R₈.
 9. The composition according toclaim 4, wherein R₁ and R₁₁ are independently chosen from hydrogen oralkyl, R₂ and R₁₂ are independently chosen from hydrogen or alkyl, R₃ ischosen from C₂-C₆ alkyl, aryl, or alkenyl, each optionally substitutedwith 0, 1 or multiple R₈, and R₄ is chosen from alkyl or aryl, eachoptionally substituted with 0, 1 or multiple R₈.
 10. The compositionaccording to claim 3, wherein R₇ is chosen from —C(O)R₉, or —CH₂OC(O)R₉.11. The composition according to claim 10, wherein R₉ is alkyl,optionally substituted with 0, 1 or multiple R₈.
 12. The compositionaccording to claim 11, wherein R₁ and R₁₁ are independently chosen fromhydrogen or alkyl.
 13. The composition according to claim 11, wherein R₂and R₁₂ are independently chosen from hydrogen or alkyl.
 14. Thecomposition according to claim 11, wherein R₃ is chosen from C₂-C₆alkyl, aryl, or alkenyl, each optionally substituted with 0, 1 ormultiple R₈.
 15. The composition according to claim 11, wherein R₄ ischosen from alkyl or aryl, each optionally substituted with 0, 1 ormultiple R₈.
 16. The composition according to claim 11, wherein R₁ andR₁₁ are independently chosen from hydrogen or alkyl, R₂ and R₁₂ areindependently chosen from hydrogen or alkyl, R₃ is chosen from C₂-C₆alkyl, aryl, or alkenyl, each optionally substituted with 0, 1 ormultiple R₈, and R₄ is chosen from alkyl or aryl, each optionallysubstituted with 0, 1 or multiple R₈.
 17. The composition according toclaim 16, wherein R₉ is chosen from —CH₃, —CH₂OCH₂CH₃, —CH₂CH₂OCH₃,—CH(CH₃)₂, —CH₂CH₂CH₂CH₃, or -cyclopropyl.
 18. The composition for thecontrol of a fungal pathogen including at least one of the compositionsof claim 9 and a phytologically acceptable carrier material.
 19. Thecomposition for the control of a fungal pathogen including at least oneof the compositions of claim 16 and a phytologically acceptable carriermaterial.
 20. (canceled)
 21. The composition for the control of a fungalpathogen including mixtures of at least one of the compositions of claim9 and another pesticide including fungicides, insecticides, nematocides,miticides, arthropodicides, bactericides and combinations thereof. 22.The composition for the control of a fungal pathogen including mixturesof at least one of the compositions of claim 16 and another pesticideincluding fungicides, insecticides, nematocides, miticides,arthropodicides, bactericides and combinations thereof.
 23. (canceled)24. (canceled)
 25. (canceled)
 26. (canceled)
 27. (canceled)
 28. A methodfor the control and prevention of fungal attack on a plant, the methodincluding the step of: applying a fungicidally effective amount of atleast one of the compositions of claim 9 to at least one of the plant,an area adjacent to the plant, soil adapted to support growth of theplant, a root of the plant, and foliage of the plant.
 29. A method forthe control and prevention of fungal attack on a plant, the methodincluding the step of: applying a fungicidally effective amount of atleast one of the compositions of claim 16 to at least one of the plant,an area adjacent to the plant, soil adapted to support growth of theplant, a root of the plant, and foliage of the plant.
 30. (canceled) 31.(canceled)
 32. (canceled)